11 The Urinary Tract Philip S. Cosgriff

11.1 Introduction 11.2 Anatomy

Despite recent technical advances in computed to- The urinary tract comprises two kidneys, individ- mography, magnetic resonance, and ultrasound ually connected to the by , imaging, nuclear (NM) has main- and a that connects the bladder to the ex- tained its crucial role in the functional assess- ternal genitalia. The kidneys are situated in the ment of the urinary tract, particularly the kidn- lumbar region at a depth of about 6 cm from the eys. surface of the back. They are positioned symmet- Indeed, techniques maintain rically about the vertebral column, their upper “gold standard” status in the diagnosis of up- and lower poles lying between the 12th thoracic per urinary tract obstruction and pyelonephritic vertebra and the 3rd lumbar vertebra respectively. scarring secondary to Each is about 12 cm long, 6 cm wide, 3 cm (UTI). Importantly, all NM renal imaging tech- thick and weighs approximately 150 grams. niques also provide an estimate of relative A cross-section through the long axis of the renal function. Absolute renal function (e.g. kidney reveals that the renal parenchyma con- glomerular filtration rate (GFR) in ml/min) can sists of a pale outer region, the cortex, and an also be measured by blood sample-based ra- inner darker region, the medulla. Unlike the cor- dionuclide methods that are superior in ac- tex, which has a relatively homogeneous appear- curacy to routinely used indicators of renal ance, the medulla consists of radially striated cones function (e.g. serum creatinine). Finally, reno- called renal pyramids, the apices of which form graphic techniques also play important roles in papillae which project into the renal sinus and the diagnosis of renovascular , re- interface with a calyx (Figure 11.1). As the re- nal transplant complications, and some lower nal artery enters at the hilum it divides into sev- urinary tract disorders such as vesico-ureteric eral interlobar arteries which themselves branch reflux. to form arcuate (“bow-shaped”) arteries which The main imaging techniques in the inves- run along the boundary between medulla and tigation of the urinary tract are renography, cortex. Smaller interlobular arteries branch off which has numerous variants, and static DMSA at right angles from the arcuate arteries heading imaging. The techniques and indications for these outwards into the cortex. Finally, the branches tests will be considered, along with their strengths from the interlobular arteries, called afferent ar- and weaknesses. A test selection guide is given in terioles, supply blood to the glomerular capillar- Table 11.1. ies.

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Table 11.1. A test selection guide for the urologist/nephrologist. See text for details. Prerequisite: renal ultrasound. When MAG3 is mentioned it is the clearly preferred radiopharmaceutical. However, 99mTc-DTPA can be used as an alternative if renal function is good Clinical question(s) Procedure to request Comment Need accurate estimate of DMSA renal scan In situations where accuracy is paramount (e.g. prior to relative renal function planned ) or where renographic estimate is likely to be technically difficult (e.g. in certain infants). No information is provided on the status of the outflow tract Suspected renal scarring DMSA renal scan Estimate of relative renal function will be routinely provided. Suspected PUJ (and/or Diuresis MAG3 renogram Estimate of relative renal function will be routinely ureteric) obstruction provided Suspected renal scarring Diuresis MAG3 renogram Scarring may be apparent on the early MAG3 images. If and suspected upper not proceed to a DMSA scan tract obstruction Suspected VUR (or UUR in Basic MAG3 renogram followed by Estimate of relative renal function will be routinely duplicated systems) Indirect provided cystogram Suspected VUR and Diuresis MAG3 renogram followed If indirect cystogram negative for reflux, repeat the test suspected upper tract by indirect cystogram without furosemide obstruction Need accurate estimate of GFR measurement (51Cr-EDTA) Could also use 99mTc-DTPA absolute GFR in ml/min Need estimate of both Basic DTPA renogram with GFR In principle, both can be measured by a single injection relative and absolute of 99mTc-DTPA. However, in children (or adults with GFR compromised renal function) it is preferable to inject 99mTc-MAG3 and 51Cr-EDTA simultaneously. Absolute GFR is measured by blood sampling

PUJ, pelvi-ureteric junction; VUR, vesico-ureteric reflux; UUR, -to-ureter reflux.

The functional unit of the kidney, the nephron, the cortex and are known as cortical nephrons. consists of a glomerulus and its attached tubule In contrast, the juxtamedullary nephrons have (Figure 11.2). There are approximately 1 million glomeruli situated in the inner third of the cor- nephrons in each kidney. The glomerulus is a tight tex. These two populations of nephrons also dif- cluster of specialized blood capillaries which serve fer with respect to the length of Henle’s loop, to filter potential urinary excreta into the tubule, juxtamedullary nephrons having relatively long thereby forming a fluid called the glomerular fil- loopswhichextenddeepintothemedulla,whereas trate. Under normal circumstances proteins and cortical nephrons have short loops which ex- other large molecules are too large to pass through tend only a short distance into the medulla the filter and return to the systemic circulation (Figure 11.2). via the efferent arteriole, perirenal capillaries, re- nal venules and, finally, the renal vein. The tubule originates as a blind sac, known as Bowman’s cap- 11.3 Physiology sule, which leads in turn to the proximal convo- luted tubule, Henle’s loop, the distal convoluted The main function of the kidneys is to conserve tubule and, finally, the collecting tubule (or duct). substancesthatareessentialtolife,andtheyshould For functional reasons, the proximal convoluted therefore be regarded as regulatory organs that tubule and Henle’s loop are sometimes collectively help maintain the constancy of the extracellular referred to as the proximal tubule and the distal fluid (ECF), in terms of both volume and com- convoluted tubule and collecting duct as the distal position. The importance of this lies in the fact tubule (or distal nephron). that most body cells will only function properly if The majority of nephrons (approximately 85%) the concentration of solutes in the tissue fluid sur- have glomeruli situated in the outer two-thirds of rounding them is kept within quite narrow limits. Figure 11.1. Gross anatomy of the kidney.

Figure 11.2. Anatomy of the nephron, showing main components (glomerulus and tubule) and associated blood vessels. The nephron illustrated has its glomerulus in the inner third of the cortex and is known as a juxtamedullary nephron, having a relatively long loop of Henle (see text).

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The importance of the kidneys in human phys- After the blood has passed through the iology can be gauged from the staggering fact that glomerulus, it enters the efferent arteriole which a pair of organs accounting for about 3% of body leads to a second capillary network woven around weight consume about 20% of all the oxygen used the tubule (see Figure 11.2), an arrangement by the body at rest. Compared to other organs, a unique to the kidney. This provides the oppor- relatively high renal blood flow (RBF) of around tunity for selected materials (particularly salt and 1100ml/min(i.e.20%ofcardiacoutput)isthusre- water) to be reabsorbed from the glomerular fil- quired to (a) provide energy for the “blood cleans- trate into the blood via the tubular cells, a pro- ing” process, (b) provide basic oxygen and nutri- cess referred to as tubular reabsorption. The main ents for the renal cells, and (c) maintain a net pos- site of all reabsorption is the proximal convo- itive glomerular perfusion pressure (GPP) for fil- luted tubule, which accounts for about 90% of tration.Collectively,theglomerulihaveahugesur- filtered sodium and 75% of filtered water. In addi- face area, so only a modest GPP (about 8 mmHg) tion to being partially filtered by the glomerulus, is required for filtration. However, a drop in GPP certain substances are also transported from the of only 15% stops filtration altogether. The main- post-glomerular blood capillaries into the lumen tenance of renal blood flow (RBF) is therefore of the proximal tubule. This process, which can be critical and there is a unique mechanism to au- considered the reverse of tubular reabsorption, is toregulate it. Moreover, a “back-up” mechanism called tubular secretion. is triggered when a change occurs that cannot be In summary, the functions of the kidney can be corrected by autoregulation (see Section 11.5.7). explained by studying the functions of an individ- Renal plasma flow (RPF), referring to the compo- ual nephron, consisting of high pressure plasma nent of blood available for filtration, is around 600 filter (the glomerulus) and fine control device (the ml/min ((1 − hematocrit) × RBF). tubule). The first stage of the urine production pro- cess is glomerular filtration, whereby plasma water and its non-protein constituents (crystal- 11.4 Radiopharmaceuticals loids) are passively separated from blood cells and protein macromolecules (colloids). Although the The site of uptake of the main renal radiopharma- glomerulus is actually considerably more complex ceuticals is shown in Figure 11.3. than a simple sieve, it behaves as if it were a filter- The pharmokinetics of agents used in nuclear ing membrane containing pores of 7–10 nm di- medicine are largely determined by their degree of ameter, excluding to a large extent any substance protein binding in plasma (Table 11.2). The min- with a molecular weight of greater than about imal protein binding of 99mTc-DTPA and 51Cr- 60 000. Normal glomerular filtration rate (GFR) EDTA means that they rapidly diffuse into the is about 120 ml/min, which means that the frac- extravascular space and are freely filtered at the tion of the plasma actually filtered (the filtration glomerulus, which represents their only excretory fraction, FF = GFR/RPF) is about 20%. The vast pathway under normal circumstances. As neither majority of this “ultrafiltrate” (over 99%) is sub- agent is reabsorbed in the renal tubule, the plasma sequently reabsorbed (i.e. reclaimed) during its clearance of these agents is effectively the renal passage along the tubule, resulting in a final urine clearance, so either can be used to determine output of about 1 ml/min. glomerular filtration rate (see Section 4.11).

Table 11.2. Properties and characteristics of commonly used renal radiopharmaceuticals Radiopharmaceutical Uptake mechanism Protein binding Extraction efficiency ARSAC DRL (MBq)

99mTc-DTPA GF <0.03 0.2 300 99mTc-MAG3 GF + TS ≈0.85 0.5 100 99mTc-DMSA DTU + GF/TR ≈0.85 0.06 80 123I-OIH GF + TS ≈0.50 0.8 20 51Cr-EDTA GF <0.01 0.2 3

GF,glomerular filtration; TS, tubular secretion; TR, tubular reabsorption; DTU, direct tubular uptake. DRL, diagnostic reference levels for injected activity in adults, as recommended by the UK Administration of Radioactive Substances Advisory Committee (ARSAC). All the molecules listed above are relatively small in size (<400 Da). 209 THE URINARY TRACT

Figure 11.3. Uptake sites of commonly used renal radiopharmaceuticals within the nephron.

Strictly, an agent with an extraction efficiency DMSA (2,3-dimercaptosuccinic acid) is used for of 1.0 is required to measure RPF but brief con- static and SPECT imaging of the kidneys, and sideration of basic renal physiology shows that 51Cr-EDTA is used for absolute measurement of such an agent is impossible. The closest that can GFR. be achieved is about 0.9 and the best substance Although OIH, MAG3, DTPA, and DMSA are in this respect is the organic compound para- cleared from the blood by different renal mech- aminohippuric acid (PAH). In fact, it was con- anisms, and with different extraction efficiencies, sidered such an important marker in renal phys- all can, in general, be used to measure relative re- iology that a new physiological term, effective nal function from imaging. The renal plasma flow (ERPF), was invented to de- phenomenon responsible for this equivalence is scribe its clearance. The substance used in nuclear glomerulo-tubular balance, which ensures that a medicine, ortho-iodohippurate (OIH), is a close change in GFR is paralleled by a change in proxi- relative of PAH, and has an extraction efficiency mal tubular reabsorption, i.e. the fractional tubu- nearly as high. Over time, the clearance of OIH lar reabsorption is maintained essentially con- has itself become synonymous with ERPF. stant. This means that, although disease may cause Radiopharmaceuticals used for gamma camera the overall filtration fraction (FF) to vary, the FF renography include 99mTc diethylenetriamine- for each kidney will be the same – explaining why pentaacetic acid (DTPA), 123I ortho- either a glomerular or tubular agent may be used iodohippurate (OIH), and 99mTc mercaptoacetyl- to determine relative renal function. triglycine (MAG3). 99mTc-MAG3 is the current 99m agent of choice. Technetium-99m and iodine-123 11.4.1 Tc-DTPA have short physical half-lives (6 h and 13 h re- spectively), monoenergetic emissions Diethylenetriaminepenta-acetic acid (DTPA) is (140 keV and 159 keV respectively) and are both a physiologically inert compound that diffuses well suited to gamma camera imaging. 99mTc- rapidly into the extravascular space following 210 PRACTICAL NUCLEAR MEDICINE intravenous injection. Its molecular characteris- 11.4.4 99mTc-DMSA tics are such that it is cleared from the plasma purely by glomerular filtration. That is, the plasma 99mTc-labeled DMSA (2,3-dimercaptosuccinic clearance is the same as the renal clearance. Dy- 99m acid) is avidly taken up by cells of the proximal namic imaging with Tc-DTPA reveals rapid tubule, with about 35% of the injected activity be- transit through the renal cortex with activity ap- ing localized (bound) in the renal cortex by one pearing in the collecting system within a few min- 99m hour. Renal uptake continues to rise, leveling off utes. Tc-MAG3 is preferred for routine renog- at about 6 hours post-injection, by which time raphy but DTPA is used when estimating individ- about 50% of the injected dose can be accounted ual kidney GFR (in ml/min) from the renogram 99m for. The remainder is cleared by other organs, pri- (see Section 11.5.2). Some centers also use Tc- marily liver and spleen, but skeletal clearance is DTPA for blood-sample-based GFR measurement 51 also a factor in infants. but Cr-EDTA is generally preferred for this pur- As the degree of protein binding is still uncer- pose (see Section 4.11). tain (probably somewhere in the range 75–90%) so is the exact renal uptake mechanism. Direct per- 123 itubular uptake of the bound fraction is probably 11.4.2 I-OIH the main effect but glomerular filtration/tubular reabsorption of the unbound fraction is also sig- Ortho-iodohippurate (OIH) – also known as nificant. “Hippuran” – has a relatively high degree of pro- DMSA is subject to degradation due to oxida- tein binding and is cleared by a combination of tion and, if uncontrolled, will result in reduced glomerular filtration and, predominantly, tubular renal uptake, increased background activity, and secretion. As a result, the extraction efficiency of high liver uptake. For this reason, the radiophar- OIH by the normal kidney (approximately 0.8) is maceutical should be injected as soon as possible much higher than that of DTPA (approximately after reconstitution with 99mTc pertechnetate. 0.2). It is thus an excellent renal imaging agent but its use is severely limited by cost and, particularly, 51 availability. The plasma clearance of 123I-OIH can 11.4.5 Cr-EDTA be used to estimate ERPF. Like 99mTc-DTPA, 51Cr ethylenediaminetetra- acetic acid (EDTA) has very low binding to plasma 11.4.3 99mTc-MAG3 proteins, is freely filterable at the glomerulus, and is not handled by the renal tubules. Extrarenal While the renal extraction mechanism of MAG3 clearance is negligible and less than 1% remains in the body 24 hours after intravenous injection. The (mercaptoacetyltriglycine) is essentially the same 51 as OIH, its clearance is only 50–60%. ERPF cannot gammaradiationfrom Crcanbeeasilymeasured be directly measured using MAG3, so a correction in a well-type scintillation detector but the pho- factor, based on correlation with OIH clearance, ton flux is too low for gamma camera imaging. In terms of radiochemical purity and stability 51Cr- needs to be used. 99m Technetium-99m-MAG3 is now the agent of EDTA is slightly superior to Tc-DTPA and is choice for all renographic procedures except ab- the agent of choice for GFR determination in sit- solute function renography (see Section 11.5.2). uations where renal imaging is not required. It is Its extraction efficiency is 2–3 times higher that extremely well established and has been validated 99mTc-DTPA but is lower than 123I-OIH. Given against inulin clearance (the ultimate substance the cost and supply problems associated with 123I for determination of GFR). products, 99mTc-MAG3 currently represents the best compromise for routine dynamic imaging. It is a simple 99mTc kit, so can be made up at any time 11.5 Renography for urgent inpatient procedures. The advantage of using 99mTc-MAG3 over 99mTc-DTPA becomes 11.5.1 Basic Renography more apparent as renal function deteriorates, but images will be of a generally higher contrast at all In basic renography a contiguous series of 10 sec- levels of renal function. ond duration digital images of the urinary tract 211 THE URINARY TRACT

Table 11.3. Renography Radiopharmaceutical 99mTc-MAG3 Application Basic renography Administered activity for 80 MBq (2.2 mCi) adults Effective dose equivalent 0.6 mSv (60 mrem) ARSAC DRL for adults 100 MBq (2.7 mCi) Pediatric activity Fraction of adult activity, based on body weight and subject to a minimum injected activity [1] Patient preparation Avoid dehydration; 500 ml oral fluid given 20–30 min before Figure 11.4. Normal renogram, showing first, second, and third injection phases. Collimator Low-energy general-purpose Images acquired Posterior dynamic study, 11.4). The so-called “time–activity curve” (TAC) 10 second frames for associated with an individual kidney is called a 30 minutes, to obtain renogram. renogram as described As a pre-processing step, the extent of patient in Section 11.5.1. movement during the study is assessed by viewing Acquired digital the dynamic data in cine mode and, if necessary, images summed every corrected using special software. The renogram 2 minutes (15 images curves and associated images can be visually in- in all) to provide visual summary of the study spected to determine whether the drainage func- 99m tion from each kidney is normal or abnormal but, Radiopharmaceutical Tc-DTPA in this basic form, renography cannot determine Application Basic renography the cause of any abnormal drainage. Administered activity for 150 MBq (4 mCi) adults Background Subtraction Effective dose equivalent 1 mSv (100 mrem) ARSAC DRL for adults 300 MBq (8 mCi) The curve derived from a kidney ROI (i.e. the raw Pediatric activity As for 99mTc-MAG3 renogram) contains a “background” contribution Patient preparation As for 99mTc-MAG3 from uptake in tissues over and underlying the Collimator As for 99mTc-MAG3 kidney that must be removed prior to estimation Images acquired As for 99mTc-MAG3 of relative renal uptake/function. Indeed, the raw renogram can be thought of as a background curve DRL, diagnostic reference level for injected activity (in adults) given in on which the true renogram is superimposed. The guidance notes issued by the UK Administration of Radioactive Substances background is composed of contributions from Advisory Committee [2]. Lower activities should be used if practical (ALARP principle) and the activity quoted above for renography should be more intravascular and extravascular activity. Further- than adequate using a modern gamma camera. more, the intravascular component is itself com- posed of contributions from renal and non-renal blood vessels. Despite many years of research in are recorded over a period of about 30 minutes this area, no single extrarenal ROI – or even com- following injection of a suitable radiopharmaceu- bination of separate ROIs – has been found that tical. The field of view should include the heart, contains intra- and extravascular components in kidneys, and at least part of the bladder. Details of exactly the same proportion as that found within the radiopharmaceuticals and their dosage levels the kidney ROI. Separate background ROIs placed are given in Table 11.3. Image processing is then perirenally (avoiding the pelvic area) or infero- performed using computer-generated regions of laterally represent the best compromise of those interest (ROI) in order to obtain graphs show- tested (Figure 11.5). ing the variation of radioactive count rate with As a result, this “simplistic” form of background time within organs and tissues of interest (Figure subtraction tends to undercorrect the renogram 212 PRACTICAL NUCLEAR MEDICINE

where the kidneys can lie at markedly different depths and orientations. Despite these potential limitations, measurement of relative renal func- tion is always an important part of any renogram report, even when, as is usually the case, the pri- mary question relates to the underlying condition (e.g. obstruction, urinary reflux, etc.).

Integral Method Up to the point at which excretion occurs, the relative uptake of glomerular or tubular agents is proportional to the individual renal clearance of the particular agent. The most straightfor- ward method of estimating relative renal func- tion therefore involves summing, or integrat- ing, the counts under the respective background subtracted renogram curves (see above) between Figure 11.5. Summed images with regions of interest (ROI) super- about 1 and 3 minutes after radiopharmaceutical imposed.SeparatebackgroundROIsareshownforeachkidney,placed injection. The relative function of the left kidney infero-laterally. A heart region (square ROI) is also shown, which is (LKF),forexample,wouldbecalculatedasfollows: used in the derivation of the output curve (see text). LKCC LKF(%) = × 100 LKCC + RKCC for background activity, as it particularly underestimates the renal vascular component. As where LKCC and RKCC are the integrated counts this effect can be asymmetric, it can occasionally from the background corrected left and right lead to a significant error in the estimate of relative renograms, respectively. renal function (see below). The starting point for integration corresponds The quality of the background subtraction totheendofthefirstphaseoftherenogram(Figure process can be crudely judged from the posi- 11.4), by which time initial mixing within the re- tion of the y-axis intercept of the background nal vasculature is complete. Note that the point of subtracted renogram, a positive value indicating inflection between the first and second phases may under-subtraction, and vice versa. Although sim- not always be seen, in which case the start point plistic background subtraction, when combined should be set at 1 minute. Elimination of activity with the integral method (see below), will pro- from the kidney actually starts just before the peak duce a good estimate of relative renal function in of the renogram, so the endpoint for integration most cases, it is preferable to treat the intravas- should be set at 30 seconds before the peak. The cular and extravascular background components more normal kidney should always be used as the separately (see Rutland–Patlak method, below). reference when setting the integration limits but a problem obviously arises when both renograms Estimation of Relative Renal Function are abnormal (i.e. significantly delayed peaks, or no peak at all). In this case, a default integration Although estimation of relative renal function is period of 1–2.5 minutes should be used. implicitinanyrenographicprocedure,arenogram would not generally be performed if this were the only clinical requirement. In that case, a DMSA Rutland–Patlak Method scan (Section 11.6) would be preferable as it is The so-called Rutland–Patlak (R–P) method was generallymoreaccurateandcertainlyeasiertoper- independently developed by the two named au- form. It should also be borne in mind particularly thors, but was popularized for renographic ap- that renographic estimation of relative renal func- plication by Rutland [3]. The method can ap- tion (using posterior imaging only) is subject to pear obscure on first encounter but its importance significant systematic error in patients with con- derives from the way in which background activity ditions such as a pelvic kidney and nephroptosis, is treated. 213 THE URINARY TRACT

Returning briefly to first principles, the ob- stitial tissues) is removed by recourse to an appro- served (“raw”) renogram derived from a kidney priate (extrarenal) background ROI (see section ROI can be thought of as a continuous function, on background subtraction, above). R(t), which is simply the sum of the true renal ac- We can thus define a renogram curve, R(t), tivity and the tissue background activity. That is: that has been corrected for extravascular back- ground activity, but not intravascular. R (t) = R(t) + B(t) t = = 1 where R (t) observed renogram, R(t) true = − = . + . . renogram, and B(t) = background curve. R (t) R (t) Be (t) f1 I (t) dt f2 I (t) The background term, B(t), is composed of 0 contributions from intravascular and extravascu- In fact, the “background ROI” method partially lar activity, so: corrects the intravascular background (by virtue R (t) = R(t) + Bi (t) + Be (t) ofthefactthataperirenalROIcontainsacontribu- tion from contained blood vessels) but it particu- = where Bi (t) intravascular background activity larly underestimates the background contribution = and Be (t) extravascular background activity. of intrarenal blood vessels. Furthermore, the intravascular component is However, if we divide both sides of the above itself composed of contributions from renal and equation by I(t) we obtain the so-called Rutland– non-renal blood vessels. Up to the time at which Patlak equation: activity starts to leave the kidney (i.e. the mini- mum transit time, t ) the kidney acts as a simple t1 1 I (t) · dt integrator with respect to its input function, I (t). R (t) = · 0 + . If the fraction of blood activity taken up per unit f1 f2 I (t) I (t) time is denoted as f1 (known as the uptake con- stant), the pure renal activity will be equal to the The motivation for this seemingly arbitrary act is total input up to time t1: that plotting R (t)/I (t) against

t1 t1

R(t) = f1 I (t)dt. I (t) · dt/I (t) 0 0

Ideally the blood input ROI should be placed over yields a straight line of slope f1 and y-intercept f2. the renal artery but this is somewhat impractical The key point is that the slope ( f1) is unaffected and it is acceptable to use the left ventricle instead. by the amount of vascular background activity The intravascular background curve, Bi (t), can present within the renal ROI, so a measurement be expressed as a given fraction, f2,oftheblood of relative renal uptake (function) based on the input curve itself, thus: respective f1 values is automatically corrected for intravascular background. The amount of blood Bi (t) = f2.I (t). background present is in fact reflected in the f2 Combining equations, we get: intercept value. It is important to emphasize that this graphical method does not account for the ex- t 1 travascular component of the background signal, R (t) = f1 I (t).dt + f2.I (t) + Be (t). so this must be separately removed, as described 0 above. In practice we find that, even using MAG3, The background subtraction process can thus be the R-P plot is non-linear over the first few min- described by the following equation: utes (Figure 11.6), due to early clearance of tracer R(t) = R (t) − [B (t) + B (t)]. from the kidney and accumulation of tracer in i e the extravascular space. To minimize the variabil- It is convenient to deal with the background ity in measured slope ( f2), the curve fitting rou- components separately, so background correction tine should be restricted to between 1 minute after isatwo-stageprocess.First,theextravascularcom- injection and a full minute before the observed ponent (mostly the result of uptake in the inter- renogram peak. If a delayed peak is observed 214 PRACTICAL NUCLEAR MEDICINE

removed on each passage through the kidney, and general mixing within the circulation. Meanwhile, activity that has been “taken up” by the kidney (a phrase that covers glomerular filtration and/or tubular secretion) passes relatively slowly along the tubular lumen (transit time ≈ 2–3 minutes) beforeemptyingintothecollectingductsand,sub- sequently, the renal pelvis. The net result of these simultaneous processes is that the radiopharma- ceutical content of the kidney (i.e. the renogram) rises sharply after the initial arrival of the injection and then more slowly. The change in slope which is often seen at approximately 45 seconds after in- jection (marking the end of the first phase) is an artifact produced by a combination of a rapidly rising renal component and a rapidly falling back- ground component. When activity starts to be eliminated from the Figure 11.6. Typical Rutland–Patlak (R-P) plot, derived from a normal background subtracted renogram (R (t)) and blood input renal pelvis (into the ureter and bladder), a sharp (heart) curve (I (t)). The renogram data (R-P plot relates to right fallinactivityfromthekidneyareawillberecorded kidney) is shown in Figure 11.9B. The fitted line straight line is which, following a rising second phase, there- superimposed on the upslope part of the curve, starting at 1 minute fore produces a peak. Excretion from the kid- after injection. The vertical marker lines on the curve indicate the ney is the dominant feature at this stage and the portion of the curve over which the line was fitted, and the equation renogram falls sharply for a few minutes. The of the line is output. If the correlation coefficient is below 0.995 the downslope thereafter becomes progressively less derivedrenalfunctionestimatewillbesubjecttosignificanterrorand steep as smaller and smaller amounts of activ- an alternative method (i.e. integral method) should be used. ity are excreted from the kidney. It is, however, important to remember that, even at this stage, the relatively small amount of radiopharmaceu- (>5 minutes) a default fitting period of 1.0–2.5 tical in the plasma which has thus far bypassed minutes should be used [4]. Compared to the the renal extraction mechanism remains in circu- integral method, the R-P method only addition- lation and continues to present an input to the ally requires an ROI to be placed over the heart, the kidney. The third phase of the renogram therefore time–activity curve from which is also required reflects continuing input and tubular transit, as for the calculation of output efficiency (Section well as loss through excretion. With this model it 11.5.4). is simple to explain how a prerenal disorder like Interpretation renal artery stenosis can give rise to an impaired third phase, and it has nothing to do with “lack When interpreting the renogram it is important of excretion”. Similarly, labeling the third phase to bear in mind that it is a record of what is left as the “excretion phase” makes it impossible to behind in the kidney (not what is “coming out”), explain the phenomenon whereby abrupt fluctu- the amount of radiopharmaceutical left behind at ations in renal blood flow (caused by anxiety or any given time depending on rate of input and pain) can produce “humps” in the latter stages of tubular transit time, as well as the rate of loss. the renogram. The normal renogram curve has three iden- tifiable phases (Figure 11.4). The first and sec- 11.5.2 Absolute Function Renography ond phases represent, respectively, arrival of radiopharmaceutical in the kidney vasculature, The most accurate and reliable way to estimate followed by uptake and transit through the both absolute and relative renal function from nephrons. The arrival of the first bolus of activ- a “single” study is to effectively combine a basic ity represents the largest “input” to the kidney. renogram with a standard (multi-sample) GFR The successive ones, resulting from recirculation measurement,thebenefitforthepatientbeingthat of non-extracted tracer, become progressively both tests can be performed in a single visit using smaller due to the large fraction of the input that is a single injection, usually 99mTc-DTPA. Although 215 THE URINARY TRACT the renogram curves will be “noisy” when renal lishment of baseline activity levels in both kidneys function is poor, relative renal function can still and bladder. Recording is continued for a couple be estimated with acceptable accuracy down to a of minutes after completion of micturition to as- GFR level of about 20 ml/min. However, in such sess natural bladder refilling. Finally, the volume situations it is wise to calculate relative function of urine voided is measured and recorded. using two different renographic methods (Section Even if there is considerable residual activity 11.5.1). in the renal collecting system (e.g. due to hy- dronephrosis) at the time when the child needs to 11.5.3 Indirect Radionuclide void, the cystogram should still be recorded as it is possible to detect gross reflux despite the mask- ing effect of this residual activity. In these circum- Indirect radionuclide cystography (IRC) is effec- stances, however, a negative study is inconclusive, tively a combination of a basic renogram (i.e. with- so should be repeated when activity has cleared out furosemide) and a subsequent relatively short from the kidneys and the bladder has refilled nat- dynamic study monitoring free voiding into a re- urally, possibly following further oral hydration. ceptacle (voiding study). The purpose of this test is Patients presenting with known/suspected up- to detect vesico-ureteric reflux (VUR), which may per tract dilatation, as well as suspected VUR, be seen during physiological filling of the bladder present a difficulty since, ideally, activity in the (i.e. during the renogram) – so-called low pressure kidneys should be cleared before the cystogram starts. Administration of intravenous furosemide reflux – or, more commonly, just after the onset of + voiding when the bladder pressure is high. VUR is (frusemide) at 15 minutes (F 15) will effectively an obvious source of upper urinary tract infection eliminate activity from the renal pelvis in patients (UTI), which can lead to pyelonephritic scarring with non-obstructive dilatation, and this has been and hypertension (see Section 11.6). advocated [5], but there are two potential disad- At the completion of a 30-minute renogram at vantages to the use for furosemide in this setting. least 80% of the injected activity should be in the Firstly, in some patients with an already nearly bladder. Clearly, the voiding phase has to be de- full bladder, intravenous furosemide will bring on layed until the patient (usually a child) feels able the urgent need to micturate and may even ne- to void on demand, which limits the method to cessitate terminating the renography study early, cooperative toilet-trained children. For younger possibly missing the chance to properly record the children, a bladder needs to be employed act of voiding. Secondly, and more importantly, and radiographic micturating it has been reported that furosemide can inhibit (MCU) is preferred over direct radionuclide cys- VUR in patients in whom it would otherwise oc- tography since it offers relevant anatomical infor- cur [6]. For the present time, a reasonable strat- mation (e.g. posterior urethral valves, ureteric di- egy would be to administer furosemide, if clini- latation) as well as the detection and grading of cally indicated, during the first appointment. If the reflux itself. However, the MCU is a distinctly un- subsequent indirect cystogram shows VUR even pleasant procedure for children with an attendant under conditions of increased urine flow, then risk of infection and a relative high radiation dose. no further study is needed. If, however, the cys- The IRC should therefore be employed whenever togram is negative, it should be repeated without possible for children over the age of about 3 years, furosemide. including follow-up patients first diagnosed using MCU. Interpretation Technique The renogram part of the study is processed in the usual manner (see Section 11.5.1) except that For the voiding part of an indirect study, study a bladder ROI is created in addition to the kidney girls are seated on an imaging chair/commode ROIs. If the third phase of the renogram has a with their backs to the gamma camera and boys “saw-tooth” appearance, it may be due to either are stood, back to camera, holding a urine bot- low pressure reflux or a peristaltic abnormality tle. The computer is set up to acquire 5 second (“hesitancy”). To make a confident diagnosis of frames for approximately 5 minutes. At least 30 reflux, the renogram peaks and troughs should seconds worth of data should be acquired before be out of phase with similar perturbations in the the child is given the signal to void to allow estab- bladder curve (Figure 11.7). 216 PRACTICAL NUCLEAR MEDICINE

For the cystogram study, a careful check for mal study shows no significant increase in renal patient movement should be made prior to im- activity in the period immediately before or after age processing. ROIs/time–activity curves are then voiding. The bladder curve shows a sharp fall in created for the kidneys and the whole of the blad- activity corresponding to voiding itself, then levels der. There is no need for background ROIs. A nor- off. An abnormal study is one that shows one or more “humps” in one or both kidney curves in the period after voiding, corresponding to a transient rise in renal activity due to reflux. The bladder may then refill with previously refluxed urine due to a “yo-yo” effect, which is a useful indicator of reflux (see Figure 11.8).

11.5.4 Diuresis Renography

Diuresis renography is the primary diagnostic tool for upper urinary tract obstruction in both adults and children, although there is still debate about the reliability of a positive test in infants with an- tenatally diagnosed hydronephrosis. An implicit Figure 11.7. Renogram curves showing bilateral “low pressure” assumption of the technique is that a true ob- reflux during normal physiological filling of the bladder. Note how struction will be present at high and low urine thepeaksintherenogramcurvecorrespondtotroughsinthebladder flow rates, thereby justifying a technique which curve, confirming retrograde flow of urine from bladder into the assesses the response of the kidney to flow rates kidneys. that are well above the normal range. In fact, the

Figure 11.8. Voiding stage of an indirect radionuclide cystogram. The peak in the left kidney (LK) curve (bold line) indicates vesico-ureteric refluxoccurringattheonsetofmicturition.Theflatrightkidney(RK)curve(--line)isnormal.Thesubsequentriseinthebladdercurve(. . . line) indicates refilling from above (i.e. the left kidney), confirming the diagnosis of left-sided reflux. 217 THE URINARY TRACT maximal total diuresis produced by intravenous tral problem of interpretation therefore lies in de- furosemide (0.5 mg/kg) in an adult patient with ciding whether the rate of fall of the renogram fol- normal renal function is around 20 ml/min, which lowing furosemide is appropriate for that kidney. is about twenty times normal. Total average urine flow rates measured after furosemide injection (0.5 mg/kg) are generally in Technique the range 8–15 ml/min, although values above 20 ml/min are not uncommon. A value of less than The method is essentially that for basic renogra- 5 ml/min (in an adult) represents an inadequate phy (Section 11.5.1), augmented by diuretic ad- diuresis (kidneys have not been sufficient stressed) ministration. Furosemide, the drug of choice, is and the associated furosemide responses should be rapidly injected at around 15 minutes after the ra- interpreted with caution. The effect of voiding is diopharmaceutical, which allows the effect of the assessed by comparison of the pre- and post-void drug on the renogram to be properly appreciated. static images. In some patients, the stasis in the If the renogram duration is 30 minutes the nota- { + = } renal pelvis will drain spontaneously immediately tion is F 15; t 30 . The furosemide dosage after voiding, thus excluding significant obstruc- is 1.0 mg/kg in infants (0–1 year) and 0.5 mg/kg tion. in children and adults. Obstructiveandnon-obstructivehydronephro- If activity remains in either renal collecting sys- sis have a characteristic appearance on the tem at the end of the study, pre- and post-void renogram post-furosemide (Figure 11.10) pro- static images should be acquired. As part of this viding that the affected kidney GFR is above 15 process, both the time of micturition and voided ml/min. The renographic response to furosemide volume are recorded, thus permitting the average can then be called non-obstructive if the fall in urine flow rate to be calculated, which provides a the curve is rapid, substantial and has a concave useful assessment of the adequacy of diuresis. slope [8]. A renogram curve which shows no (or The dynamic images should be processed as for very little) decline post-furosemide is classified basic renography, with the additional calculation as obstructive. Drainage patterns falling between of output efficiency (OE) for quantifying the effect these extremes represent an equivocal response, of furosemide [7]. In order to use the normal range and will be seen in 10–15% of cases, usually the re- values given in Table 11.4, the measurement must sultofimpaired(individual)renalfunctionand/or be made at 30 minutes (OE30), and the furosemide gross renal pelvic dilatation. A fourth response given at between 15 and 20 minutes. The hard (the so-called “Homsy sign”) is sometimes seen copy output should include the input and output where an initial positive renographic response to curves from which the OE measurement was de- furosemide is followed by a premature leveling off rived (Figure 11.9). or a rise (Figure 11.11), which is indicative of high flow or intermittent obstruction [9]. Output effi- Interpretation ciency measurement is particularly useful in the The renographic response to furosemide depends assessment of equivocal responses and will reduce on a number of factors, including individual re- the rate to about 5%. Simple curve indices such nal function, baseline urine flow rate (hence hy- as clearance half-times do not have sufficient dis- dration), flow rate induced by diuretic (hence criminatory ability in this context [10]. furosemide dosage), renal pelvic volume at time The small group of patients whose results of administration, elasticity of the wall of the renal remain equivocal after output efficiency anal- pelvis, and degree of ureteric peristalsis. The cen- ysis should be retested, this time giving the furosemide at 15 minutes before the radiophar- maceutical {F − 15; t = 20}, based on the fact Table 11.4. Classification of output efficiency that furosemide produces its maximal effect about measured at 30 minutes (OE30), with furosemide given 15 minutes after injection [9]. Some centers use at 15 minutes F − 15 renography as a first-line technique, but this does not permit a before and after assess- OE30 (%) Diagnosis ment, and requires routine furosemide adminis- >78% No obstruction + <70% Obstruction tration to all patients. With F 15 renography, the 70–78% Equivocal decision to administer the drug can be delayed un- til the need is clear. Some pediatric centers give the A

B

Figure 11.9. A Summarized image data from a 30-minute dynamic study in an adult, whereby 180 images are condensed down to 15; each new image thus representing 2 minutes of data. The study clearly demonstrates the normal passage of injected tracer (99mTc-MAG3) from blood to urine via the kidneys. There is also some hepatobiliary clearance of MAG3, hence the liver uptake. B Curve data presentation for reporting, showing a the background subtracted renograms, b a selected of summed images covering the 30-minute study (with ROIs superimposed on one image), c, d the left and right output (o/p) curves (for calculation of output efficiency), derived from the respective renograms and the cumulative input curves (see Piepsz et al [4]). Relative renal function was calculated as: left = 63%, R = 37%, and output efficiency at 30 minutes (OE30) calculated as: left = 96%, right = 95%. The right kidney relative function was slightlybelowthelowerlimitofnormalbuttherenogramshowsnoevidenceofoutflowtractobstruction.Furosemidewasgivenat16minutes (prompting accelerated washout) but both renogram curves were already clearly descending at this point.

218 219 THE URINARY TRACT

Pelvic (and hence whole kidney) transit times will be prolonged in cases of obstructive and non- obstructive hydronephrosis, and will not therefore provide a differential diagnosis. In fact, the whole kidney mean transit time (WKMTT) is directly re- lated to the patient’s state of hydration and is there- fore meaningless unless this is strictly controlled. The parenchymal mean transit time (PMTT) is unaffected by the state of hydration, but is depen- dent on urine flow rate, a first order correction for which is provided by subtracting the minimum PTT from the mean PPT to yield the corrected PPT (CPTT). In the absence of other conditions known to cause prolonged transit (e.g. renova- Figure 11.10. Possible renographic responses to furosemide in- suclar hyptertension), a CPTT of greater than 4 jected15minutesafterinjectionoftheradiopharmaceutical{F + 15, minutes in a patient with renal pelvic dilatation t = 30} in a kidney with a dilated collecting system. A “washout” indicates obstructive nephropathy. phenomenonisobservedinnon-obstructedsystems,causingarapid fall in the renogram curve. Deconvolution Techniques The shape of the renogram is dependent on the furosemide immediately after the radiopharma- rate of tracer input, tubular transit time, and rate ceutical (F + 0) in an attempt to keep the study of loss. The fact that the input function varies duration to a minimum [11], but this has the same with time is a further complicating factor since disadvantages as the F − 15 approach. it is subject to physiological effects that are un- Renographic tests also have a useful role in related to renal function. Also, for a given input the assessment of lower ureteric obstruction, par- function, there will be a spread of transit times ticularly in excluding significant obstruction in due to the fact that nephrons of a given type vary patients with dilated ureters on IVU. Although in length, and there are two different populations diuresis renography was primarily designed to di- of nephrons within the kidney (see Section 11.2). agnose upper tract obstruction, the concept of The renogram is therefore a complex curve from furosemide-induced washout can also be applied which transit times cannot be directly measured. to the ureter. It should be noted that the pres- The renographic time-to-peak gives a crude esti- ence of lower tract disorders also has an impor- mate of parenchymal transit time, but a purer rep- tant bearing on the interpretation of upper tract resentation of renal transit is required for its accu- obstruction [12]. rate measurement. This purer function, “hidden” within the renogram, is called the renal retention function (RRF), and mathematical techniques are 11.5.5 Transit Time Analysis required to extract it. The RRF can be thought of as an internal prop- The main clinical application of renal transit times erty of a particular kidney that determines how is in the diagnosis of upper urinary tract obstruc- the input (blood curve) is converted into an out- tion. Briefly, when upper tract obstruction oc- put (i.e. the observed renogram) (Figure 11.12). curs, the pressure gradient between the glomeru- Mathematically speaking, the input function is lus and the obstruction site is altered (i.e. the convolved with the retention function to pro- pressure in the renal pelvis and the tubular lu- duce the output function. The problem there- men rises). The kidney responds by passively in- fore is to deconvolve the input function from creasing the reabsorption of salt and water in the output function to produce the retention the proximal tubule, triggered by the obstruction- function. associated pressure difference between the tubu- The convolution operation is represented by the lar lumen and the peritubular capillary. The net following equation: result is that any non-reabsorbable solute (like t OIH, DTPA or MAG3) will be concentrated in a smaller volume of filtrate, thus prolonging its R(t) = I(τ) · H(t − τ)dτ tubular (parenchymal) transit time. 0 a

b c

Figure 11.11. MAG3 renogram study in a 46-year-old female patient with a distal left ureteric stenosis and a blocked , showing a summary of dynamic images covering a period of 30 minutes, b renogram curves, and c contemporary IVU. The images a show a grossly hydronephrotic kidney with specific abnormality in the upper pole. There is evidently impaired drainage from both upper tracts. The curve data b show an equivocal response to furosemide on the left. The right kidney renogram shows the “Homsy sign” where an initial response to furosemide is followed by a pronounced rise. The IVU c shows the pigtail catheter in place in the lower pole of the left kidney, which is hydronephrotic. The left ureter is dilated. The right kidney also shows impaired drainage, as well as cortical thinning and scarring.

220 221 THE URINARY TRACT

Figure 11.12. The kidney depicted as a linear system. Input is converted to output via the kidney’s impulse response (or retention) function. Knowledge of the actual input and output functions A allows calculation, via deconvolution, of the retention function. This represents the response of the kidney (depicted as ?) to a simpler, idealized, input B . where R(t) = response of kidney to input, I(τ), The mean transit time, MTT, can be calculated H(t) = retention function (also called the impulse according to the expression: τ response function or transfer function), and is ∞ a continuous variable representing time. H(t) dt Solving the above equation for H(t) is called de- MTT = 0 . convolution and several techniques are available, H(0) including the matrix method [13], transform methods [14], constrained optimization [15] and, H(0), the amplitude of plateaued retention func- most recently, a method based on differentiation tion at t = 0, will equal unity by definition since of the Rutland–Patlak plot [16]. The matrix H(t) is a fraction. The mean transit time is there- method of deconvolution is certainly the most fore simply the total area under the RF curve (up to widely used clinically, but is subject to a number the point at which it crosses the time axis) divided of potential pitfalls. by the initial plateau height. Negative excursions The retention function, H(t), represents the re- of the retention function are non-physiological, sponse of the system to a unit impulse, i.e. a rect- and any data points giving rise to such variations angular (“delta”) function having unit area but should be set to zero. infinitesimally narrow width (see Figure 11.12). The main assumptions made in the foregoing Such an input cannot be achieved in clinical prac- discussion are that the response of the kidney to a tice but could be approximated by a rapid bo- series of impulse inputs is simply the sum of the lus injection given directly into the renal artery individual impulse responses. Since a continuous with no recirculation. The renal retention func- input function can be regarded as a series of im- tion, H(t), can therefore be thought of as the pulse inputs, the corresponding output function renogram that would be produced if we could (i.e. the renogram) can therefore be predicted by perform such an idealized injection. It therefore convolving the input function with the impulse represents the simplest form of renogram imag- response function. Secondly, that ERPF, GFR, and inable and should provide a clearer insight into urine flow rate must all remain constant for the the pathophysiological processes affecting renal duration of the test. Normal physiological fluctu- transport mechanisms than that derivable from ations in urine flow rate are such that they are ef- the background subtracted renogram. The general fectively smoothed out using an acquisition frame shape of the normal retention function is shown in time of 10–20 seconds and can usually be ignored. Figure 11.13. Fluctuations in renal blood flow can be minimized 222 PRACTICAL NUCLEAR MEDICINE

Figure11.13. Thenormalretentionfunctionshowingatheinitialvascularspike,andbthe“plateaued”versionwithvascularspikeremoved. The spread of transit times, illustrated by the superimposed transit time spectrum, gives rise to the gradual rather than the abrupt fall in the retention function. T1 = minimum transit time, T2 = mean transit time, and T3 = maximum transit time, which refer to the renal ROI (either parenchymal or whole kidney) from which they were indirectly derived. by ensuring that the patient is as relaxed and com- is helpful to do this routinely, thereby providing fortable as possible, excellent injection technique complementary information in all cases. Since a (i.e. avoiding pain and anxiety), and conducting heart ROI/TAC is already required for the mea- the study in a quiet environment. In short, the surement of output efficiency (Section 11.5.4) and success of transit time analysis is dependent on at- the Rutland–Patlak plot (Section 11.5.1), the only tention to detail, and close adherence to published addition to the processing method is the definition validated methods. of parenchymal ROIs.

Comparison of Transit Time Analysis and 11.5.6 Perfusion Renography Furosemide Response Perfusion renography describes a technique The renographic response to furosemide (see Sec- whereby a short (40 second) period of relatively = tion 11.5.4) and parenchymal transit time mea- rapid fast framing (frame rate 1/s) precedes the surement (Section 11.5.5) are complementary basic renogram acquisition. The resultant “split- techniques, since they assess obstructive uropa- frame” study thus comprises a “perfusion phase” thy and the obstructive nephropathy, respectively. followed by a “function phase”.The technique has Although direct comparisons have shown that been used in the context of renal transplantation transit time measurement and furosemide re- (Section 11.5.8) and renovascular hypertension sponse perform similarly in the diagnosis of upper (RVH). For the latter, it was reasonably assumed tract obstruction, the furosemide test is regarded that assessing the relative perfusion of the kid- as the primary diagnostic tool as it provides a neys might hold the key to diagnosing renal artery more direct assessment and is easier for urol- stenosis (RAS), but clinical results (with and with- ogists to comprehend. After relief of obstruc- out ACE inhibition) have been disappointing. The tion, urinary drainage from the renal pelvis will techniqueisnowofpurelyhistoricalinterestinthis improve before any associated improvement in context, having been replaced by captopril renog- parenchymal function, so diuresis renography will raphy. therefore provide an earlier indication of surgical outcome. 11.5.7 Captopril Renography It is perfectly feasible to derive transit time data from an F + 15 renogram (using data acquired The diagnosis of RVH (i.e. functionally signifi- before the administration of furosemide), so it cant RAS) is essentially retrospective, so the key 223 THE URINARY TRACT question relates to prognosis: can renography re- ies. A significant fall in the contribution of the liably predict those patients who will benefit from affected kidney (after captopril) is taken as an in- revascularization, in terms of blood pressure re- dication of functionally significant unilateral RAS. sponse and/or improvement in renal function? To A significant fall has been stated as a shift of >5% understand the role of captopril in this setting re- (i.e. 5 percentage points) to a value below 40% quiresbriefconsiderationoftherenin-angiotensin [17]. The use of relative function alone as a moni- system. toring tool is of course subject to the fundamental When a severe (>70%) narrowing of the re- disadvantage that an observed change may be due nal artery causes a reduction in renal blood flow to improved function on one side or deterioration which cannot be “compensated” by the autoregu- on the other. It would therefore appear advan- lation system, the glomerular perfusion pressure tageous to perform absolute function renography falls. As a result, the kidney secretes an enzyme (Section11.5.2)withandwithoutcaptopril.Reno- called renin that, in turn, acts on a plasma protein graphic time-to-peak and/or parenchymal mean called angiotensinogen to form angiotensin I. An- transit time (Section 11.5.5) are also routinely cal- giotensin converting enzyme (ACE) then acts on culated in some centers. angiotensin I to produce angiotensin II, which is a Disease prevalence is a key issue in this context, potent vasoconstrictor at the arteriolar level, act- so it is essential to select only those hypertensive ing directly upon peripheral and intrarenal blood patients with a medium-to-high pre-test probabil- vessels to raise systemic and renal perfusion pres- ity of RVH (e.g. moderate-to-severe hypertension sure. Captopril, a so-called ACE inhibitor, blocks in a young patient (25 years), sudden onset, sud- the conversion of angiotensin I to angiotensin II, den worsening of previously controlled hyperten- thereby removing the mechanism by which the af- sion, unresponsive to antihypertensive drug ther- fected kidney’s perfusion pressure is maintained, apy). causing individual kidney GFR to fall in patients Varying sensitivities and specificities have been with RVH. reported for captopril renography in the diag- nosis of RVH, largely explained by the varying Technique prevalence of the disease in the populations stud- ied, and differences in scintigraphic methodology. In its conventional form, captopril renography ac- A pooled average of recent reports (for 99mTc- tually comprises two separate renograms, one to DTPA) gives a sensitivity of 76% and specificity act as baseline and another one hour after oral of 90%, based on changes in renographic parame- administration of 25 mg captopril. The order in ters. Analogous results for the post-captopril study which the studies are conducted varies between alone were 92% and 66% respectively [18]. Gen- centers but both are routinely performed when the erally, the sensitivity of the test falls as the level of objectiveistomeasurethechangeinrenalfunction function in the affected kidney decreases. following ACE inhibition. If the baseline study is Captopril renography is less reliable in the eval- performed first, the whole test can be completed uation of bilateral RAS. Apart from the fact that in one day without hospital admission. changes in renographic parameters expressed as The main intrarenal effect of ACE inhibition is left-to-right ratios become difficult to interpret, on GFR and it is therefore logical to use a glomeru- RVH arising from bilateral RAS is much less renin lar imaging agent such as 99mTc-DTPA in this con- dependent than unilateral RAS. As a consequence, text. However, the quality of the DTPA kidney im- the effect of ACE inhibition on renal function is age falls dramatically as renal function decreases, less marked, and sensitivity of the captopril test is making changes in renal function difficult to de- therefore reduced. In bilateral disease, the test will tect in these patients. Tubular agents such as 123I- only tend to identify the more stenosed kidney as OIH and 99mTc-MAG3 have better imaging prop- abnormal, and angioplasty on this side alone may erties but the observed renographic changes are not ameliorate the hypertension. sometimes more difficult to interpret. Interpretation 11.5.8 Transplant Renography Several renographic parameters have been tested Transplant renography is simply perfusion renog- in this setting. As a minimum, relative function raphy (Section 11.5.6) applied to the renal (Section11.5.1)shouldbeestimatedforbothstud- transplant. The gamma camera is positioned 224 PRACTICAL NUCLEAR MEDICINE anteriorally over the allograft, usually located in tion (in various clinical settings) and the diagnosis the iliac fossa (Figure 11.14). of renal scarring in the presence of urinary tract in- For the perfusion phase, ROIs are created for the fection (UTI). Indeed, the DMSA scan is regarded transplant itself, a background area, and adjacent as a reference technique in both areas. iliac artery. The “perfusion index” (PI) is derived UTI is associated with vesico-ureteric reflux and from the associated time–activity curves (Figure pyelonephriticscarring.ThedetectionofVURwas 11.15). For the function phase, the transplant ROI discussed in Section 11.5.3. In this section we con- is used with the background ROI to generate a sider the effect of urinary reflux on the kidney (re- transplant renogram. The typical renogram from flux nephropathy), which is investigated primarily a functioning transplant is similar in shape to that using renal ultrasound and 99mTc-DMSA imag- derived from a normal native kidney but often has ing. The aim is to detect renal scarring, which has a delayed/flattened peak due, in part, to prolonged prognostic implications for the development of parenchymal transit of tracer. hypertensionandend-stagerenalfailure,although An isolated PI value will not reliably differ- the latter is very rare. About 10% of children with entiate the main acute medical complications of UTI will develop scars, usually as a result of the transplantation (acute rejection and acute tubular first episode and, of these, about 10% will develop necrosis). Repeating the renogram every 2–3 days consequential hypertension in later life. during the early transplant period is more useful SPECT imaging of the kidneys should theo- (sudden fall in the PI trend can predict impending retically improve the detection of renal scars but rejection) but the fall may only precipitate the rise there is no consensus on the clinical usefulness of in serum creatinine by 24 hours, and performing SPECT imaging in children. SPECT studies invari- frequent renograms on all transplant patients is a ably detect more defects than planar imaging but huge undertaking, even for a well-resourced nu- doubt remains as to the true clinical significance clear medicine department. In both Europe and of these additional “abnormalities”,particularly as the USA, routine transplant renography thus be- there are more normal variants to consider. Pre- came perceived as a high cost/small benefit proce- dictably, inter-observer variability is higher than dure and was already in slow decline when a new for static imaging, although this may represent a breed of immunosuppressive agents appeared in “learning curve problem”.The addition of SPECT the early 1980s, prompting a further fall in popu- imaging obviously extends the total imaging time larity due the fact that (a) acute rejection became considerably so will be resisted in pediatric circles less frequent and more controllable and (b) the until such time as the clinical benefits are clearer. associated mild nephrotoxity associated with ci- In summary, SPECT imaging of the kidneys is not closporin A made diagnosis of rejection based on currently recommended for routine clinical use. PI even more difficult. The more routine use of and developments in other imaging modalities techniques (especially Doppler ultra- 11.6.1 Static Imaging Technique sound) means that transplant renography is now rarely used to diagnose rejection. It is, however, General and child-specific procedure guidelines still used to investigate suspected surgical and uro- have been developed [19, 20]. High-resolution im- logical complications (Figure 11.16). ages should be obtained in the anterior, poste- rior, and posterior oblique projections. Details of the acquisition protocol are shown in Table 11.5. 11.6 Static and SPECT Renal The basic relative uptake measurement is sim- 99m ple to perform but must be corrected for both Imaging Using Tc-DMSA background activity and for differences in kid- ney depth. The latter correction is less important The uptake mechanism of DMSA was discussed in in children than adults but is recommended for Section11.4.Clearly,arenalagentthatiseffectively all patients. The correction is achieved by sim- fixed in the renal cortex provides an ideal means ply calculating the geometric mean of the ante- of estimating relative function without interfer- rior and posterior count rates for each kidney ence from overlying pelvicalyceal activity. The two and expressing the result as a ratio. If a dual- main indications for 99mTc-DMSA imaging are head gamma camera is used the anterior and thus accurate measurement of relative renal func- posterior views can be acquired simultaneously. Figure 11.14. Normal anterior perfusion images A, acquired at 7 days post-transplant showing aortic bifurcation, iliac arteries, and renal transplant. The 15 3-second images were derived from the acquired dataset of 45 1-second images, initiated a few seconds after bolus injection of 99mTc-DTPA. The summarized function phase B show uptake in the transplant and prompt excretion into the adjacent bladder. The 15 1.3-minute frames were derived from an acquired dataset of 60 20-second frames. (Images courtesy of Dr M. Keir, Royal Victoria Infirmary, Newcastle.)

225 226 PRACTICAL NUCLEAR MEDICINE

Table 11.5. Renal imaging Radiopharmaceutical 99mTc-DMSA Application Static renal imaging for assessment of relative renal function and pyelonephritic scarring Administered activity for 80 MBq (2.2 mCi) adults Effective dose equivalent 0.7 mSv (70 mrem) Pediatric activity As for 99mTc-MAG3 Patient preparation None Collimator ow-energy, high-resolution Images acquired Images should be acquired at approximately 3 hours post-injection, and include anterior, a posterior, left and right posterior oblique views. Use appropriate acquisition (hardware) zoom for children

sion, but is most easily calculated as:

RKF(%) = 100 − LKF.

DMSA imaging is thus technically simple to per- form, allows a wide time window in which the im- ages can be acquired (2–6 hours post-injection), and only requires the patient to keep still for b 2–3 minutes at a time. It provides a more accu- rate measurement of relative renal function than Figure 11.15. Processing of the perfusion part of a transplant that obtained from renography (Section 11.5.1), renogram showing a position of whole kidney (K), background (Bkg) particularly when renal function is severely im- andiliacartery(IA)ROIsandbassociatednormaltime–activitycurves. paired and/or when a kidney is rotated or in an The kidney curve is background subtracted. After area normalization unusual position. Multicenter audit studies have ofthekidneyandiliacarterycurves,theperfusionindex(PI)isdefined shown that measurement of relative renal func- as the ratio of areas under the two curves (iliac artery/kidney) up to the peak of the iliac artery curve. In this example, the PI is 1.3. tion measurement from DMSA images is highly reproducible [21, 22].

The contribution of the left kidney to to- Interpretation tal renal function is thus calculated using the formula: DMSA uptake within the kidney reflects the distri- bution of functioning renal cortical tissue. A mod- LKF(%) = 100 × LKGM/(LKGM + RKGM). ern gamma camera fitted with a high-resolution collimator will visualize some of the internal ar- LKGM and RKGM are the geometric means chitecture of the kidney, so normal uptake is not of anterior and posterior counts from the generally uniform. Calyces will often be seen, par- left and right kidneys, after background ticularly if dilated, as may the columns of Bertin subtraction. (Figure11.17).Extrinsiccompressionofthelateral Right kidney relative function (RKF) can be in- aspect of the left upper pole by the spleen is often dependentlycalculatedusingananalogousexpres- seen (Figure 11.18) and fetal lobulation may be Figure 11.16. Perfusion A and function B images showing a non-perfused, non-functioning graft (photopenic area overlying the right iliac artery) due to early postoperative infarction. (Images courtesy of Dr M. Keir, Royal Victoria Infirmary, Newcastle.)

227 228 PRACTICAL NUCLEAR MEDICINE

Figure11.17. NormalDMSAimageinan8-year-oldgirlwithhistory Figure11.19. NormalDMSAimageina3-year-oldgirlwithhistory of UTI. The lateral aspect of the mid pole of the left kidney shows of UTI. The lower pole outline of the left kidney (arrowed) shows prominent columns of Bertin. segment of concavity typical of fetal lobulation, which is a normal variant. The mid pole appears to bulge slightly as a result.

A pyelonephritic scar is generally manifest as a segmental area of reduced uptake. Other space- occupying lesions (e.g. cyst, tumor) produce areas of reduced uptake but will usually be of different shape, and should be identifiable on renal ultra- sound or CT.The DMSA scan is certainly the “gold standard” for diagnosis of scarring, but renal ul- trasound plays a pivotal role in the general man- agement of patients with febrile UTI. The DMSA scan may show a patchy appearance during the in- flammatory stage of acute UTI, which will either resolveorprogresstofocalareasofreduceduptake. In turn, focal parenchymal defects may disappear or degenerate into permanent scars (Figure 11.20). It is therefore important to be aware of the clinical history (i.e. date of last UTI) when interpreting DMSA images. Although the presence of segmen- Figure 11.18. Normal DMSA image in an adult, showing extrinsic tal cortical defects on an “acute” DMSA scan in- compression by the spleen in the left upper pole. The left kidney also dicates a high (approximately 80%) probability of shows prominent calyces (photopenic area) in the mid and lower permanent renal damage, the defect should not be poles, which are also normal variants. called a “scar” unless it is still evident at 6-month follow-up. seen in young children (Figure 11.19). It is clearly Although the measurement of relative DMSA important to recognize these normal variants in uptake is clearly useful in this setting (for baseline order to avoid false positives. Indeed, visual in- assessment and monitoring), there is no clear cor- terpretation of static DMSA images is subject to relation between relative renal function and pres- significant inter-observer variability and has led ence or extent of scarring. Indeed, up to 35% of to the production of guidelines [20]. patients with unilateral scarring will have evenly 229 THE URINARY TRACT

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