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Nuclear Renal Imaging in Acute Pyelonephritis Hirsch Handmaker Patients with acute pyelonephritis may present with a spectrum of clinical signs and symptoms. There are f e w noninvasive diagnostic studies, however, to confirm or exclude this diagnosis. A small number of patients, generally those with severe disease, will demonstrate radiographic changes on excretory urography, but the lack of sensitivity of the IVP in early, acute pyelonephritis is well documented. Several radionuclide techniques have been proposed to assist in the earlier detection of this clinical problem including imaging with Mercury-197 chlormerodrin, Gallium-67 citrate, Technetium-99m glucoheptonata, Technetium-99m DMSA, and, more recently, Indium-111 labeled white blood cells. The success of the renal cortical imaging agents as well as those which localize in infection are described in this report. There appears to be a complimentary role for the cortical imaging agents and the radiopharmaceuticals which localize in bacterial infection. Cortical agents offer the advantage of specific assessment of functioning renal tissue and a convenient, rapid method for following the response to treatment in a noninvasive manner. A pattern is described which may be diagnostic; correlation with Gallium-67 citrate or Indium-111 WBCs may increase the probability of infection as the cause for the cortical abnormality. The measurement of differential renal function using cortical agents provides additional information to assist the clinician in predicting the late effects of infection. Improved sensitivity and specificity, and a reproducible method for following the response to therapy in patients with acute pyelonephritis are the advantages of the techniques described. "Pyelonephritis, like virtue, is easier to talk about than to define." origin" with little to suggest the kidney as the site of infection. Conventional radiographic and ultrasonic examinations generally are accepted as of limited value in acute pyelonephritis; nuclear medicine procedures rarely are mentioned in review articles dealing with imaging strategies in patients with sudden onset of fever, flank pain and pyuria/bacteruria.2 This review summarizes the use of nuclear renal imaging in acute pyelonephritis and its efficacy. Edward H. Kass ~ CUTE bacterial pyelonephritis produces a A variety of problems for primary care physicians, pediatricians, and diagnostic specialists. The seriousness of the disease is punctuated by the evidence that chronic renal disease may be a frequent late result of acute infection and the possibility that a direct relationship exists between acute pyelonephritis and renal hypertension. It often is difficult to confirm or exclude renal parenchymal involvement by a bacterial infection on the basis of the patients clinical presentation. Fever, leukocytosis and bacteriuria alone do not differentiate simple infection of the bladder and/or ureters from actual renal involvement. Conversely, patients with acute pyelonephritis may present as a "fever of unknown From the Nuclear Medicine Service, Children's Hospital of San Francisco, San Francisco, Calif. Address reprint requests to Hirsch Handmaker, M.D., Nuclear Medicine Service, Children's Hospital of San Francisco, 3700 California Street, San Francisco, Calif. 94118. Portions of this work were originally presented at the 26th Annual Meeting of the Society of Nuclear Medicine in June, 1979. Supported in part by General Research Support Grant 5 501 R R 05470-08 and funds made available by the Board of Directors, Children's Hospital of San Francisco. 91982 by Grune & Stratton, Inc. 0010-2998/82/1203-0003501.00/(9 246 M A T E R I A L S A N D METHODS Several radiopharmaceuticals have gained support for use in the diagnosis and evaluation of inflammatory diseases of the kidney. Gallium-67 citrate is injected intravenously in a dose of 3-6 mCi (5 0 #Ci/kg) or according to height and weight tables when used in pediatric patients. ~ Some authors have advocated the early (6 hr) imaging of patients suspected of having acute pyelonephritis.4 We prefer to wait 24-48 hr because of the significant normal renal uptake and excretion which occurs in the first 24 hr and may interfere with the proper evaluation of the kidneys. Current scintillation gamma cameras using multiple photopeak techniques provide high quality images despite the multienergy emissions of this radiopharmaceutical. Tomographic scanners or other tomographic devices may reduce interpretive difficulty but are mentioned in only one publication on this subject. 4 Renal cortical imaging can be accomplished with either the intravenous injection of Technetium-99m glucoheptonate, in a dose of 10-15 mCi, again adjusted for height and weight in pediatric patients, or Technetium-99m DMSA, 3-5 mCi in adults and similarly adjusted for pediatric patients. Dynamic perfusion images in a posterior position are useful in evaluating the perfusion and function of the kidneys. No specific perfusion pattern is seen in acute pyelonephritis; increased blood flow may occur. Seminars in Nuclear Medicine, Vol. XII, No. 3 (July), 1982 NUCLEAR RENAL IMAGING Recording of the dynamic and static images on computer systems should be an adjunct to the study; quantitative information can be obtained, particularly with the Technetium-99m DMSA s!udy, and may be of value in assessing patients in the acute and recovery stages of acute pyelonephritis. After an appropriate delay, generally 90-120 min after injection, the highest possible resolution images are obtained using a high resolution parallel hole low energy collimator and posterior oblique pinhole views as has been described elsewhere. 5 Pinhole views are essential to delineate the striking pattern of acute pyelonephritis. Indium-Ill labeled autologous white blood ceils have recently been introduced as a method for evaluating acute pyelonephritis. 6 The WBC's are injected intravenously, usually 500 ~Ci-lmCi, and imaging is performed at 18-24 hr. 247 G A L L I U M - 6 7 CITRATE RP 2 7 RESULTS We have had the opportunity in the past 6 yr to evaluate over 60 patients to confirm or exclude the diagnosis of acute pyelonephritis. Patients studied were from 1 wk to 50 yr of age, and had clinical findings ranging from "fever of undetermined origin" to bacteruria, flank pain and renal colic. Ten of these patients had abnormal renal cortical scans that assisted in confirming the diagnosis of acute pyelonephritis. Five of these patients with abnormal cortical scans also had abnormal Gallium-67 citrate images. No attempt was made to perform both Gallium-67 citrate and renal cortical imaging studies in all patients in this series. There were no false negative renal cortical studies in our series. Figure 1 demonstrates the findings in a 27yr-old female with right flank pain, fever, bacteruria, and pyuria. The 48-hr Gallium-67 citrate scan was suspicious for increased uptake in the region of the right kidney but background activity in the abdomen made it difficult to confirm the diagnosis of acute pyelonephritis. Drip infusion nephrotomogram and IVP were normal. A renal cortical study was performed with Technetium-99m DMSA which revealed a focal defect in the mid-portion of the right kidney, with an abnormal left-to-right uptake ratio. The right posterior oblique pinhole view revealed a distinctive striated "flare" defect in the perihilar region of the right kidney. This pattern was observed in 4 of the 10 abnormal patients. The right kidney defect disappeared following 2 wk of antibiotic therapy and on the repeat study the left-to-right ratio had returned to nearly normal. Figure 2 demonstrates the studies in a 9- R Anterior 9/6/74 t R L/R = 1.27 ,~ t RP 27 ...... 9 ] k "LPO PO,te.or Posterior RPO Posterior RPO 11/11/74 L/ O LPO Fig. 1. A 27-yr-old female with right flank pain, fever and pyuria. (A) 48-hr Gallium-67 scan shows increased uptake in the right renal area; abdominal activity, liver and contralateral renal uptake made confirmation of infection difficult. (B) Tc-99m DMSA images on September 6, 1974 following gallium scan reveal right midrenal defect; pinhole oblique suggest "'flare" pattern (see Discussion). Followup scan after treatment on November 11, 1974 reveals return to normal appearance. Quantitative ratios similarly show return of function ("L/R'). mo-old male with recurrent urinary tract infections, pyuria, and fever. His excretory urogram reveals delayed visualization on the right with some dilatation of the right collecting system at 15 min. The 48-hr Gallium-67 citrate study shows diffuse increased activity in the entire right kidney compatible with either acute pyelonephritis or perinephric abscess. The Technetium-99m DMSA study demonstrates multifocal 248 HIRSCH HANDMAKER 79~00.003: 15 minutes 79-00-003 9 m o . O~ i: LPO Posterior RPO Fig. 2. A 9-mo-old male w i t h recurrent urinary t r a c t infections, pyuria and fever. Excretory urogram reveals (A) delayed visualization of the right kidney at 5 min, (B) some dilatation of the right collecting system at 15 min. (C) Posterior Gallium-67 scan reveals diffusely increased uptake in the right kidney. (D) SemTc DMSA scan reveals multifocal areas of decreased activity with the RPO pinhole images showing striated "flares" compatible w i t h acute pyelonephritis. disease on the right with several striated "flares" of decreased activity at the mid and lower pole of the right kidney, extending from the hilum to the periphery of the kidney. This patient demonstrates the "hot kidney" on the Gallium-67 citrate study, nonspecific in nature, that may produce confusion. The patient responded to antibiotic therapy in a fashion compatible with acute pyelonephritis. Figure 3 demonstrates ill-defined increased Gallium-67 citrate uptake in the left kidney region of a 2-mo-old female who presented with fever and a left flank "mass." The high background abdominal activity at 48 hr prevents differentiating abscess from pyelonephritis or tumor. Ultrasonic examination demonstrates enlargement of the kidney without other specific abnormalities. Excretory urogram shows somewhat diminished visualization of the left kidney and collecting system. The Technetium-99m glucoheptonate study demonstrates multifocal defects in the mid and lower poles of the left kidney suggestive of acute pyelonephritis, with overall diminished uptake compared to the normal right NUCLEAR RENAL IMAGING 249 79-00-523 2mo. ~ B Longitudinal Prone 79-00-523 2mo. ~ 79~00-523 2mo.~ LPO C kidney. Surgical biopsy and blood cultures confirmed the diagnosis of E. coli pyelonephritis. Figure 4 demonstrates a striking multifocal striated "flare" pattern of acute pyelonephritis in an 8-yr-old male studied with Technetium-99m DMSA. The child had severe vesicoureteral reflux, unresponsive to antibiotic treatment; the Posterior RPO Fig. 3. A 2-mo-old female w i t h f e v e r and left flank " m a s s . " (A) E x c r e t o r y urogram reveals faint visualization of t h e left kidney and collecting system. (B) Sonogram demonstrates an enlarged left kidney. (C) Posterior Gallium-67 scan shows ill-defined increased activity in t h e left renal area, (D) S~mTc glucoheptonate study demonstrates multifocal defects in the inferior and midportion of t h e left kidney. Biopsy and blood cultures confirmed E. coil pyelonephritis. patient did not improve and a surgical reimplantation of the ureter was carried out. Figure 5 demonstrates the serial DMSA scans documenting the dramatic improvement in the patient in Fig. 4 resulting in a nearly normal appearance of the right kidney on the latest follow-up study. The left-to-right ratio also HIRSCH HANDMAKER 250 75.00-397 76-00-966 8 cr 99m Tc-GH 4/3/75 99mTc-DM AS LPO Posterior RPO Fig. 4. An 8-year-old male with severe right vesicoureteral reflux and recurrent infections. (A) ~=Tc DMSA images reveal typical " f l a r e " pattern of decreased activity from the hilum to the periphery, multifocal in nature, on the right ("hot spots" in the midline of the posterior view are ..... 61517 r LPO !POSTERIOR RPO 10 cm markers). Fig. 6. A 2-yr-old female with fever and pyuria. Upper panel shows m"Tc glucoheptonate images that are normal in posterior parallel hole high resolution view, but show a discrete defect in the upper pole of the right kidney on RPO pinhole view. Note the persistent pelvic and ureteral activity at 2 hr on the GHA images. Followup study with DMSA in the convalescent period (lower panel) confirmed the response to antibiotics, with no urinary activity seen, and normal cortical scan. 7/6/76 Fig. 5. Initial, postoperative reimplantation and 3-me pinhole images (RPOs) in patient described in Fig. 4 demonstrating improvement and return to nearly normal 8emTc DMSA uptake in kidney following surgery for reflux. returned to normal and gave little evidence of residual renal damage from the reflux and pyelonephritis. Figure 6 demonstrates a right upper pole defect in acute pyelonephritis in a 2-yr-old female performed with Technetium-99m glucoheptonate and the normal followup study performed with Technetium-99m DMSA after 2 me of antibiotic therapy. This complete return to normal offered good assurance to the referring physician that the infection was controlled with no residual disease. Note the ureteral activity which persists on the Technetium-99m glucoheptonate study 99 min after the injection. It also should be noted that the defect is clearly seen only in the right posterior oblique pinhole view. This is especially true in young patients with small kidneys. Figure 7 demonstrates the area of interest selection for a Technetium-99m DMSA quantitative study for the patient discussed in Fig. 2. Computer generated left-to-right ratio (1.5/1) indicated the severity of the disease. (Normal = 0.9-1.1/1) DISCUSSION Patients suspected of having acute pyelonephritis rarely demonstrate radiographic findings either on plain film or excretory urography. Imaging procedures have not been as helpful in confirming the presence of acute pyelonephritis as they have in other disease processes. Conventional radiographic techniques are useful in identifying anomalies of the genitourinary tract that predispose the patient to infection, such as vesicoureteral reflux, but direct evidence of infection is uncommon particularly in the early phases of the disease. In two series, abnormal excretory urograms were found in only 24% 7 and 28% 8 of patients with acute pyelonephritis. There is some disagreement between these two authors, in fact, regarding the exact nature of the findings: Elkin 9 describes "small volume" pelvis and Silver 8 dilated and distorted pelvicalyceal structures. Other urographic findings include: (1) renal enlargement, (2) lowered urine flow and associated delayed pyelogram, (3) diminished concentration of contrast material, (4) nonobstructive dilatation of the ureter, and (5) infrequently, prolonged or absent visualization of the nephrogram. NUCLEAR RENAL IMAGING Fig. 7. 251 A r e a of interest selection and computation of the 2-hr differential renal function in the patient in Fig. 2 (see Discussion). Ultrasound examination of the kidneys is extremely useful in confirming renal or perirenal abscesses. These are seen as cystic areas of necrosis in or adjacent to the renal parenchyma; ultrasound is of little value in confirming acute pyelonephritis, however. Enlargement of the kidney was the sole abnormal finding in a few patients in one series/~ Ultrasound can be used to guide a biopsy needle if histologic or fluid confirmation is required in either pyelonephritis or other infectious processes. The use of Gallium-67 citrate in the diagnosis of acute pyelonephritis was originally proposed by Kessler et al. t~ Subsequent publications have verified the reliability of this procedure. 4'12'13 Gallium-67 citrate localizes in polymorphonuclear leukocytes after being cleared from the blood where it is bound with transferrin. It also has been documented to localize in areas of high tissue lactoferrin concentration. ~4 As in other sites of bacterial infection, therefore, increased gallium uptake can be expected in bacterial infections within the kidney. The accuracy of 86% in distinguishing upper tract from lower tract infection at 48 hr reported by the Kessler group in a later paper J5 compares favorably with the more invasive, traditional confirmatory studies for acute pyelonephritis, including ureteral catherization and bladder-washout. Difficulty with the Gallium-67 citrate study arises from the inability to distinguish intrarenal from extrarenal (i.e., perinephric) infectious processes, and the normal concentration of the radiopharmaceutical by the kidneys. 16'17 A variety of other diseases involving the kidneys, including acute tubular necrosis and vasculitis have also been reported to produce increased renal gallium concentration.~8 Renal cortical radiopharmaceutical agents were first suggested as potentially useful in detecting acute pyelonephritis by Davies. ~9 The advantages of using Technetium-99m cortical agents include highest resolution images for detection of parenchymal abnormalities, ready availability of the radiopharmaceuticals, and the capability for simultaneous quantitative evaluation of renal function in acute and posttreatment follow-up periods. Either of the commonly used renal cortical radiopharmaceuticals, Technetium-99m glucoheptonate 2~ or Technetium99m DMSA is acceptable, though the latter remains unapproved by the FDA some 8 yr after its appearance in the literature. 5'22 DMSA is the preferred material for renal cortical imaging as no confusing urinary excretion is encountered in the pelvicalyceal structures 2 hr after injection, even in patients with obstructed or dilated collecting systemsd Our experience with cortical agents suggests that on occasion a specific pattern is seen which may be typical for acute pyelonephritis. The striking striated or "flare" of decreased renal activity, often multifocal in nature, radiating from the pelvicalyceal structures toward the periphery of the cortex has been seen in several patients with acute pyelonephritis. (Figs. 1, 2, and 4) This corresponds to the angiographic and pathologic findings of peritubular edema, increased interstitial pressure and plugs of cellular debris within the tubules characteristic of acute pyelonephritisfl3'24 Other scintigraphic findings, such as diminished overall function or focal cortical defects in the presence 252 HIRSCH HANDMAKER of a normal IVP and ultrasound examination increase the probability of acute pyelonephritis. The synergistic use of a combination of these procedures including the cortical scan, Gallium67 citrate or Indium-1 11 white blood cell scan, ultrasound and/or urography should permit a higher degree of specificity for the diagnosis of acute pyelonephritisY '26 No patient in our series with proven acute pyelonephritis had a normal renal cortical scan. For this reason, and its convenient 2-hr completion time, we prefer to perform this imaging procedure first. If an abnormal study, nonspecific in nature, results from the renal cortical scan, in association with the ultrasound finding of a cystic mass in or adjacent to the renal parenchyma, Gallium-67 or Indium-111 WBCs may be used to further characterize the abnormality as pyogenic or nonpyogenic. When the gallium or WBC scan has been performed first, as in patients with fever and no localizing signs or symptoms, it may be necessary to further characterize abnormalities as renal or extrarenal in nature with a renal cortical scan. This wilt assist in determining whether the "hot kidney" is due to pyelonephritis or perinephric abscess. Following our initial experience with Technetium-99m DMSA in renal cortical imaging, it seemed logical that its similarities to the organomercurials would permit its substitution in this technique for assessing differential renal function. 27 Using a modification of Raynaud's Mercury-197 "fixation" technique, 28 we presented and published our clinical results and concluded that D M S A was a satisfactory agent for this purpose. 29 Subsequently, in vitro animal and human confirmation have been published by several authors. 3~ Either simple left-to-right ratios or more elaborate differential kidney uptakes may be performed from 2 to 24 hr after injection of the material. While it is not the purpose of this report to describe the quantitative techniques, they are useful additions to the renal cortical scan in assessing the degree of renal impairment produced by acute pyelonephritis. The second part of this two issue series has a detailed review of current approaches to quantitative imaging. They can be readily performed at the time of the initial imaging and add no additional radiation exposure or invasiveness to the procedure. The ability to determine and monitor the return of function in the involved kidney following medical or surgical treatment in a convenient manner is a significant factor favoring the use of D M S A in these patients (Fig. 5). Indium-1 1 l-labeled autologous leukocytes have been found useful in this disease entity. This technique appears to be superior to Gallium-67 citrate imaging in that the radiopharmaceutical is not normally excreted by the kidneys; renal uptake of any intensity, therefore, will be indicative of inflammatory disease. 6 Greater experience with this radiopharmaceutical will be necessary to ascertain its exact role in the evaluation of patients suspected of having acute pyelonephritis. The techniques described should aid in the prompt and accurate diagnosis of acute pyelonephritis where it is clinically in question. Renal cortical imaging should clarify the confusion that often surrounds patients with nonspecific imaging results such as enlarged kidneys on ultrasound, "hot kidneys" on gallium scan and clinical symptoms of infection. It should not be necessary to postulate the existence of an entity such as "acute lobar nephronia" in patients with bacterial infection of the renal parenchyma, nor to perform angiography) 3 The patient in Fig. 3 fulfilled all the "criteria" for A L N , and, as might be expected, had typical biopsy and bacteriologic evidence of acute pyelonephritis. ACKNOWLEDGMENT The author wishes to express his thanks and appreciation to RoseAnn Anderson and Carol Lewis for their diligence and technical skill, to Bradford Young and Raymond Fay for their cooperation and advice, and Pete Peterson for his tenacity in completing the preparation of this manuscript. REFERENCES 1. Kass EH: The search for asymptomaticpyelonephritis. N Engl J Med 287:563-564, 1972 2. Wicks JD, Thornbury JR: Acute renal infections in adults. Radiol Clin North Am 17:245-260, 1979 3. Bell EG: Appendix, Tables A-2, A-3, in Handmaker H, Lowenstein JM (eds): Nuclear Medicine in Clinical Pediat- rics. New York, Society of Nuclear Medicine, 1975, pp 270-271 4. MendezJr. G, Morillo G, Alonso M, et al: Gallium-67 radionuclide imaging in acute pyelonephritis. Am J Roentgenol 134:17-22, 1980 5. Handmaker H, Young BW, Lowenstein JM: Clinical NUCLEAR RENAL IMAGING experience with 99'~Tc-DMSA (Dimercaptosuccinic acid), a new renal-imaging agent. J Nucl Med 16:28-32, 1975 6. 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Brugh III R, Gooneratne NS, Rittenberg GM, et al: Gallium-67 scanning and conservative treatment in acute inflammatory lesions of the renal cortex. J Urol 121:232-235, 1979 14. Hoffer PB, Huberty J, Khayam-Bashi H: The association of Ga-67 and lactoferrin. J Nucl Med 18:713-717, 1977 15. Hurwitz SR, Kessler WO, Alazraki NP, et al: Gallium-67 imaging to localize urinary-tract infections. Br J Radio149:156-160, 1976 16. Frankel RS, Richman SD, Levenson SM, et al: Renal localization of Gallium-67 citrate. Radiology 114:393-397, 1975 17. Handmaker H, Anderson RA: Renal imaging and pyelonephritis (Letter to Editor). West J Med 123:63, 1975 18. Kumar B, Coleman RE: Significance of delayed 67Ga localization in the kidneys. J Nucl Med 17:872-875, 1976 19. Davies ER, Roberts M, Roylance J, et al: The renal scintigram in pyelonephritis. Clin Radiol 23:370-376, 1972 20. McRae J, Barry AC, Valk PE: Renal scintigraphy using Tc-stannous chloride gluconate. Aust N Z J Med 1:291, 1971 253 21. 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Raynaud C: A technique for the quantitative measurement of the function of each kidney. Semin Nucl Med 4:51-60, 1974 29. Handmaker H: Simplified differential renal function studies using Technetium-99m DMSA, in Raynaud C (ed): Proceedings of llcCollogue International sur La Fixation Renale Du Mercure Radioactif. Paris, 1975, pp 225-232 (in French) 30. Daly M J, Jones W, Rudd TG, et al: Differential renal function using Technetium-99m dimercaptosuccinic acid (DMSA): In vitro correlation. J Nucl Med 20:63-66, 1979 31. Beekhuis H, van Luyk WHJ, Piers DA: Differential renal function using Technetium-99m dimercapto-succinic acid (DMSA); in-vivo correlation. (Letter to Editor) J Nucl Med 20:898-899, 1979 32. Taylor AT, Lallone RL, Hagan PL: Optimal handling of dimercaptosuccinic acid for quantitative renal scanning. J Nucl Med 21:1190-1193, 1980 33. Rosenfield AT, Glickman MG, Taylor K J, et al: Acute focal bacterial nephritis (acute lobar nephronia). Radiology 132:553-561, 1979