Altered Anion Handling by Choroid Plexus in Renal Insufficiency

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Kidney International, Vol. 23 (1983), pp. 387—392

Altered anion handling by choroid plexus in renal insufficiency

JULIO V. RIVERA, RAFAEL RAMIREZ-GONZALEZ, and JULIO MORALES

The Nuclear Medicine and Nephrology Services, Veterans Administration Medical and Regional Office Center, San Juan, Puerto Rico

Altered anion handling by choroid plexus in renal insufficiency. Abnor- drugs were administered within 15 mm of each other. Imaging mal localization of 99mTc pertechnetate was detected in the choroidwas accomplished with a dual probe nuclear rectilinear scanner plexus of patients with renal insufficiency despite the administration of potassium perchiorate. This was found in 8 of 21 studies on patients on (Model 084 Ohio, Technicare Corporation, Cleveland, Ohio). conservative medical treatment, in 35 of 41 studies in patients on Eighty-four brain scans were performed in 70 patients with hemodialysis, in 12 of 22 studies in renal transplant recipients, and in 1 chronic renal insufficiency, which included 21 studies of pa- of 5 with acute renal insufficiency, but not in any of 33 persons free of tients receiving conservative medical treatment, 41 of patients renal disease. Abnormal retention of pertechnetate was also observed on chronic hemodialysis, and 22 of renal transplant recipients. in the salivary glands of 21 renal patients. The increased localization of 99mTc pertechnetate could not be related to high blood levels ofFor comparison, we also reviewed brain scans performed on 33 radioactivity, altered protein binding, increased erythrocyte labeling or patients referred for various neurological problems. Each one to impaired gastrointestinal absorption of potassium perchlorate. It is of these patients immediately followed or preceded a chronic proposed that this finding represents a manifestation of choroid plexus renal patient on the day's schedule and formed the "control" dysfunction resulting in altered handling of anions by this organ. A possible relation to neurological disease in chronic renal insufficiency is group. During a later period, brain scans were performed on suggested. five persons with acute renal insufficiency. Scans were reviewed by two observers, one of whom was Conservation des anions par les plexus choroldes modifiée lors deunaware of the patient's clinical condition. The presence of l'insuffisance rénale. Une localisation anormale de pertechnetate devisualization of the choroid plexus was noted and classified as a été détectée dans les plexus choroides de malades ayant une insuffisance rénale malgré l'administration de perchlorate de potassium. slight (+), moderate (+ +), or marked (+ + +). Notation was Cela a été trouvé dans 8 sur 21 etudes de malades sous traitementalso made as to whether or not the parotid glands, which may conservateur medical dans 35 sur 41 etudes de malades en hémodialyse, also concentrate this material, were clearly visible in these dans 12 sur 22 etudes de receveurs de transplant renal, et dans 1 étude studies. sur 5 malades atteint d'insuffisance rénale aigue, mais non chez 33 personnes indemnes de maladie rénale. Une retention anormale du In five renal patients in whom the choroid plexus was pertechnetate a egalement été observée dans les glandes salivaires de 21 visualized despite medication with perchiorate, the study was parmi les malades rénaux. L'augmentation de Ia localisation du pertech- repeated following oral administration of strong iodine solution, netate de 99"Tc ne pouvait pas être reliée aux concentrations sanguines 0.5 ml, US Pharmacopeia, Rockville, Maryland. Iodide is also de radioactivité élevées, a une alteration de Ia liaison protéique, a une augmentation du marquage érythrocytaire, ni a un trouble de l'absorp- usually effective in blocking the uptake of pertechnetate by the tion gastrointestinale de perchlorate de potassium. II est propose que ce choroid plexus. Eight renal patients with elevated serum creati- résultat représente une manifestation de dysfonctionnement des plexusnine had brain scans following the administration of s9mTc choroIdes, resultant d'une alteration de Ia conservation des anions par diethylenetriaminepenta-acetic acid (DTPA). This complex is cet organe. Une relation possible avec l'atteinte neurologique decommonly used for brain scanning to avoid localization of l'insuffisance rénale chronique est suggeree. radioactive technetium in the choroid plexus. To determine if labelling of erythrocytes or altered plasma protein binding with mTc could play a role in the visualization The choroid plexus, site of cerebrospinal fluid production,of the choroid plexus we performed the following experiments: actively concentrates ssmTc pertechnetate, a material often In ten patients including six of the chronic renal group and used in the performance of brain scintigraphy [1]. To avoid thefour controls, blood samples were secured 30 mm after the interference of pertechnetate localization with the interpreta-administration of pertechnetate (99mTc) for determination of in tion of brain scans, potassium perchlorate is given routinely tovivo labelling of erythrocytes. Erythrocytes were separated by persons undergoing this examination. centrifugation and washed with normal saline. The proportion Following the casual observation of visualization of theof activity per unit of volume of whole blood, erythrocytes, and choroid plexus on pertechnetate brain scans in several patientsplasma was determined. with endstage renal disease, we undertook a systematic study to determine the frequency of this finding and its possible causes.

Methods Received for publication June 18, 1981 Brain scans were performed 1 to 2 hr following the adminis- and in revised form July 16, 1982 tration of 20 to 30 mCi of 9smTc pertechnetate by the intrave- 0085—2538/83/0023—0387 $01.20 nous route and 300 mg of potassium perchlorate orally. The two © 1983 by the International Society of Nephrology

387 388 Rivera et a!

Dialysis

Control

Ca C 25 C, 0 Transplant Medical C .0a, E 45% .0 z 0 .0a, E 23% z

IltIM'ihjI IsMtl

Fig. 1. Frequency and degree of choroid plexus visualization on brain scan in patients with chronic renal insufficiency according to treatment modality, acute renal failure, and nonrenal. Symbols relating to choroid plexus visualization are: LI, none; ,small;ll, moderate to marked. <2 2to2.9 3to 5.9 6toQ.9 >10

Serum creatinine, mg/dI In nine renal patients on maintenance hemodialysis and ten normal persons, the in vitro association of ssmTc pertechnetate Fig. 2. Frequency and degree (LII, none; ii, small; 1111, moderate to marked) of choroid plexus visualization on brain scan in patients with with serum proteins was examined by the equilibrium dialysischronic renal disease. The majority (38 of 48) of those whose serum method described by Hays and Green [21. creatinine was >3 mg/dl showed abnormal concentration. Twelve A possible role of blood radioactivity levels in choroid plexus patients with abnormal localization and serum creatinine <2 were visualization was tested in the following two observations: recipients of renal transplants. In this group the finding could not be In 20 unselected subjects, including patients with acute and related to the level of creatinine (Table 1). chronic renal insufficiency and nonrenal patients, the whole blood concentration of ssmTc radioactivity was determined at the time of starting the brain scan, and it was related to the degree of visualization of the choroid plexus. sample (cpm/mlIM2 of body surface corrected to 0 time) was In three patients with chronic renal insufficiency requiringdetermined in duplicate in a well scintillation counter. hemodialysis the level of blood radioactivity was determined 1 hr after injection, immediately preceding brain scanning. He- Results modialysis was then carried out for 4 hr at the end of which Figure I summarizes the results of brain scans in each group. blood radioactivity determination and brain imaging wereFifty-six brain scans in renal patients including subjects in each repeated. treatment category showed a concentration of pertechnetate in To view the distribution of activity in the salivary and thyroid the choroid plexus, although this was not seen in any of the glands and the large vessels at the base of the neck, scintillationcontrol group. The finding was by far most pronounced and camera views were taken 30 to 180 mm after the injection offrequent in patients on hemodialysis. 99mTc pertechnetate in six renal patients and seven controls. The frequency of visualization of the choroid plexus correlat- Potassium perchlorate was taken by these patients immediatelyed with the level of serum creatinine which may be considered after the 30-mm scintiphoto had been obtained. One of theman index of severity or duration of disease (Fig. 2). Patients was given lemon and later a full meal, and viewing was repeatedwhose serum creatinine was above 3 mg/dl (38 of 48) usually after 5hr. concentrated pertechnetate in the choroid plexus, but the To test the possibility that impaired absorption of perchloratemajority of those with serum creatinine below that level did not. might explain the results observed, the gastrointestinal absorp-The exception was 12 transplant recipients whose creatinine tion of sodium s9mTc pertechnetate, a very similar ion, waslevel was normal or slightly elevated at the time of examination. studied. Five normal adults and five patients with chronic renalIn this group the serum level of creatinine was 1.5 0.5mg/dl failure requiring hemodialysis were given 2 mCi per 70 kg bodyamong those in whom the choroid plexus was seen and 1.8 weight of sodium s9mTc pertechnetate orally at least 2 hr after 1.1mg/dl among those in whom it was not visualized (Table 1). the last meal. Heparinized blood samples were secured 30, 60,Also to be noted is that only one of five patients with acute renal and 120 mm afterward. The radioactivity of each whole bloodfailure (serum creatinine 4 to 10 mg/dl) had this finding. Choroid plexus in renal insufficiency 389 U r;' 4tS • •.4i . • I5 • •1 • It. • *1 a•,•,.?.. at a V W 4. .9't'.W.: — —" ../, t • It' . ! U': •i- — .% 5..5, I • S , •1% -n-

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Fig. 3. Brain scan of patient with chronic renal insufficiency. A Lateral H: I view, 1 hr after administration of 99"Tc pertechnetate and potassium perchiorate. Whole blood radioactivity, 36,500 CPM/ml. B Posterior and lateral views after 4 hr of hemodialysis (7 hr after s9mTc pert echne- tate). Whole blood radioactivity was 12,600 CPM/ml.

Table 1. Serum creatinine and choroid plexus visualization in A relation could not be established between plasma radioac- transplant recipients tivity and visualization of the choroid plexus in the 20 patients Serum creatinine, in which this observation was recorded (Table 2). Neither was N mg/dla this apparent in the three patients where reduction of blood activity resulted from hemodialysis. In these patients the cho- Choroid plexus not visualized 8 1 8 —+11 roidplexus was visualized just as clearly when the lower blood Choroid plexus visualized 6 1.5 0.5 radioactivity level was obtained as it was initially (Fig. 3). The choroid plexus was visualized in all five patients given Abbreviation: N, number of transplant recipients. the strong iodine solution. These patients had also previously aDifferenceis not statistically significant. shown abnormal uptake when perchiorate was given. None of the eight renal patients given s9mTc DTPA showed concentra- Table 2. Blood radioactivity related to choroid plexus visualization tion in the choroid plexus. N Range' Mean SD' The activity ratio between erythrocytes and plasma in ten patients did not differ significantly between the renal (0.28 Choroid plexus not visualized 13 9 to 183 130 73.8 0.11)and control groups (0.34 0.11; Table 3). The values Visualized 7 48 to 250 92 46.8 obtained are similar to those reported by others [21. The association of ssmTc pertechnetate with serum proteins Abbreviation: N, number of patients. aNetcounts per minute x 103/ml whole blood. examined by equilibrium dialysis in patients with renal insuffi- The difference between the two groups is not statisticallyciency and normal persons is summarized in Table 4. The significant. values obtained in the normal persons were similar to those also 390 Riveraet al

Table 3.Distribution of ssmTc pertechnetate in blood Table 4. Bindingof 99mTC pertechnetate to atbumin CP Serum albumin N RBC/Plasmaa visualization N % bound gidi Control 4 0.34 0.11 0 Normal 10 83.3 l.3 5.7 0.3

Renal 6 0.28 0.11 4 Renal insufficiency 9 68.2 7.6 3.6 0.6 Abbreviations: CP, choroid plexus; N, number of patients. Abbreviation: N, number of patients. aDifferenceis not statistically significant. Difference is statistically significant (P > 0.001).

reported by Hays and Green [2]. Lower values for proteinfrom decreased renal excretion was considered, but seems binding, which relates to hypoalbuminemia found in severalunlikely for several reasons. The fact that the finding was subjects, were found in the renal patients. inconstant in persons with renal insufficiency suggests the Review of all the brain scans on renal patients and controlscontribution of other factors. Higher blood concentrations of with potassium perchlorate premedication also revealed persist-perchlorate, a very similar ion, may well also occur in these ent activity in the salivary glands in 16 patients with renalpatients, augmenting its inhibitory effect on pertechnetate ex- insufficiency and in five controls. Fourteen of the 16 renaltraction. Also contrary to this explanation is the observation patients also showed localization in the choroid plexus. that correction of renal insufficiency by renal transplantation We looked specifically in four of the six renal patients fordoes not appear to alter the finding. The infrequency of this localization of pertechnetate in the salivary and thyroid glands;finding in patients with acute renal insufficiency and its persis- persistent localization up to 3 hr was observed (Fig. 4). In onetence after the reduction of blood radioactivity levels by patient salivary gland activity was not discharged after stimula-hemodialysis thus cannot be explained. Neither does in vivo tion with lemon juice and a full meal. In each of the four patientslabelling of erythrocytes appear to be a factor. In some cases, the choroid plexus showed considerable activity 1 hr afterthe data presented may support the alternate possibility of administration of 99mTc pertechnetate. In all control patientsreduced avidity of pertechnetate for serum albumin which pertechnetate was discharged by the salivary and thyroid glandsmight facilitate its localization in the plexus. following the administration of potassium perchiorate. A reduced effect of perchlorate on the transfer of pertechne- The level of radioactivity in the blood after oral administra-tate into the choroid plexus resulting from impaired gastrointes- tion of ssmTc pertechnetate in normal persons and renal patientstinal absorption may be considered but appears unlikely. Gen- was similar at each interval tested. eralized malabsorption is not prevalent among patients with The mean and 1 SD of blood radioactivity for five normal andrenal insufficiency [61. None of the patients studied presented five renal patients, respectively, at each time interval testedwith clinical evidence of gastrointestinal disease. Our finding of was as follows: 5.92 x l02.61 x ICS and 7.67 x io 2.3 xnormal absorption of pertechnetate, an ion very similar to l0 at 30 mm; 6.29 x l01.1 x l0 and 6.73 x i052.16 xperchlorate, also weighs against this possibility. l0 at 60 mm; 5.83 x lO 8.30 x 10 and 5.56 x 101.85 x It should not be surprising that 99mTc DTPA did not behave l0 at 120 mm. The differences between normal and renalsimilarly to 99mTc pertechnetate considering its different molec- patients are not statistically significant (X2) (Fig. 5). ular configuration and size. The handling of this complex by the Localization of pertechnetate in the choroid plexus of renalchoroid plexus is likely to be different. Incidentally, we suspect patients was detected in the presence of various diseases,that the widespread use of this complex in brain scanning may including polycystic kidney disease. All patients examined whobe a reason why this abnormality has not been observed by exhibited neuropsychiatric syndromes had this finding, but soothers. did many who had no obvious neurological problems. The salivary and thyroid glands as well as the choroid plexus possess transport mechanisms capable of extracting various Discussion anions from the blood. Following intravenous administration, We have observed that, despite the administration of perchlo-s9mTc pertechnetate promptly localizes in the salivary and rate or iodide, the choroid plexus is visualized frequently onthyroid glands. Maximal concentration is reached in the thyroid Tc pertechnetate brain scan in patients with chronic renalin approximately 30 mm [7, 81. The administration of perchlo- failure but generally not in patients with acute renal insufficien-rate normally produces prompt release of pertechnetate from cy. This finding is unusual under normal conditions, particular-both glands. ly the marked localization that permitted visualization of the The finding of persistent localization of pertechnetate in the extension of the plexus into the fourth ventricle in manysalivary and thyroid glands in the patients who also retained it patients [1, 3—5]. in the choroid plexus suggests a widespread abnormality in the The increased concentration of pertechnetate in the choroidhandling of this ion by cellular elements. This distribution is plexus may be interpreted as an alteration in the function of thissimilar, but not identical, to that reported by Aneri, Loug- organ, consisting of augmented transport of this ion into thechampt, and Bassett [9] in patients receiving stannous citrate or lining epithelium or its decreased ability to transfer the materialpyrophosphate prior to the administration of pertechnetate. into the cerebrospinal fluid or back into the blood [41. One may postulate that retention of tin or other substances Thepossibility that increased choroid plexus localization ofrelated to renal failure could be the cause. These could lead to pertechnetate is the result of high blood concentration resultingchanges in the cellular macromolecules. Choroid plexus in renal insufficiency 391

C E c)0

C E 0

Control Renal

Fig. 4. 99'"Tc pertechnetate localization in the salivary and thyroid glands 30 mm after administration (upper)and180 mm after the addition of potassium perchlorate (lower), in a patient with normal renal function and in one with chronic renal insufficiency. Persistent localization in the salivary and thyroid glands is evident in the latter. Arrows point to the thyroid and salivary glands.

Grantham [101 described alterations in the transport of fluidfunction have been related to the neurological pictures accruing and organic ions by renal tubules and altered cerebrospinal fluidin plexus papilloma [131, hydrocephalus [14], African trypano- caused by uremic sera. He relates this to aryl acids, substancessomiasis [151, lupus erythematosus [16], Goodpasture syn- which are actively transported by the choroid plexus, thedrome [17], and immune complex disease [18]. thyroid, and the kidney. Neuropsychiatric disorders are among the most frequent and The fact that the abnormality is found in patients withserious complications of chronic renal disease. The pathogene- polycystic kidneys as well as in other renal diseases arguessis of many of these disorders is poorly understood. Cerebral against a possible immunological mechanism. Persistence ofscintigraphy in some patients has revealed specific abnormali- these findings after adequate renal function has been restoredties such as chronic subdural hematoma, venous sinus thrombo- by transplantation appears to indicate remaining cellular dam-sis, cerebral infarction, or abscess. In other patients nonspecific age or failure of its cause to be removed by this procedure. alterations have been observed and attributed to cerebral We considered the possible clinical implication of our find-edema [191 or to the binding of pertechnetate to erythrocytes in ings. Physiological studies [11, 12] in our opinion have thor-the presence of abnormal concentration of tin [9]. In most oughly documented the role of choroid plexus function andpatients, however, the brain scan is normal. cerebrospinal fluid circulation and in the metabolic homeostasis Radionuclide cisternography has revealed abnormal cerebro- of the central nervous system. Alterations in choroid plexus spinal fluid dynamics in some patients with dialysis dementia 392 Riveraet at

10 1 References 1. WITCOFSKY RL, JANEWAY R, MAYNARD CD, BEARDEN EK, -k81l SCHULTZ JL: Visualization of the choroid plexus on the techne- E tiums9m brain scan. Arch Neurol 16:286—289, 1967 2. HAYS MT, GREEN FA: In vitro studies of 9smTc pertechnetate .>610 binding by human serum and tissues. J NucI Med 14:149—158, 1973 0 3. Go RT, PTACEK JJ: Localization of ssmTc in the choroid plexus of the fourth ventricle. J Nucl Med 14:352—353, 1973 410 4. SILBERSTEIN AB, LEVY LM: 9SmTc localization in the choroid plexus. Radiology 95:529—532, 1970 21O 5. FAYEN Wi: Potassium iodide block of choroid plexus visualization in technetium brain scan (letter). J Nuci Med 12:98, 1971 6. EKROYAN G: Pathophysiology of chronic renal failure and the uremic syndrome, in Pathophysiology of the Kidney, edited by 0 30 60 90 120 KURTZMAN NA, MARTfNEZ-MALDONADO M. Springfield, Illinois, Time after administration, miii C. C. Thomas, 1977, pp. 854—855 7. SHIMMINS JG, HARDEN RM, ALEXANDER WD: Loss of pertechne- Fig. 5. Blood radioactivity following oral administration of sodium tate from the human thyroid. J Nucl Med 10:637—640, 1969 "Tc pertechnetate in five patients with chronic renal failure 8. HECK L, LATHROP K, GOTTSCHALK A, HARPER PV, FULTZ M: (0—) and five normals (0 )(meanand 1 SD). The levels attained Perchlorate washout of pertechnetate from the thyroid gland (ab- by the two groups at each interval are similar indicative of an absence of stract). J Nuci Med 9:323, 1968 malabsorption in the renal patients. 9. ANERI D, LONCHAMPT MF, BASSETT JY: The effect of tin on the tissue distribution of 99mTC sodium pertechnetate. Radiology 124:445—450, 1977 10. GRANTHAM JJ: Fluid secretion in the nephron: Relation to renal failure. Physiol Rev 56:248—258, 1976 [20]. If the abnormality in the handling of pertechnetate by the 11. CSERR HF: Physiology of the choroid plexus. Physiol Rev 51:273— choroid plexus described in this study is a sign of dysfunction of 311, 1971 this organ which may also affect physiologically important 12. WRIGHT M: Active transport of iodide and other anions across the choroid plexus. J Physiol 240:535—566, 1974 substances, then these two findings lend support to the previous 13. FAYAN JA, COWAN Ri: The effect of potassium perchiorate on the suggestion by Grantham [10] linking abnormality in cerebrospi- uptake of ssmTc pertechnetate in choroid plexus papillomas. A nal fluid secretion to the pathogenesis of neurological syn- report of two cases. J Nucl Med 12:312—314, 1971 dromes in patients with renal insufficiency. Longitudinal stud- 14. MILHoit.T TH: Evidence of choroid plexus absorption in hydro- ies are needed to determine the time sequence of onset of these cephalus. N EngI J Med 283:286—289, 1970 15. ORMEROD WE, SEGAL MB: The function of the choroid plexus in findings and their possible relation to the neurological the brain of rabbits infected with the sleeping sickness trypano- syndromes. some. J Trop MedHyg 76:120—125, 1973 16. GERSHWIN ME, HYMAN LR, STEINBERG AD: The choroid plexus in CNS involvement of systematic lupus erthematosus. J Pediatr Acknowledgments 87:588—590, 1975 17. MCINTOSH RM, COPACK P, CHERNAK WB, GRISWOLD WR, WElL Portions of this study were presented at the Second International R, Koss MN: The human choroid plexus and autoimmune nephri- Congress of the World Federation of Nuclear Medicine and Biology in tis. Arch Pathol Lab Med 99:48—50, 1975 Washington, D.C., September 1978. The authors thank E. Cora de 18. HARBECK Ri, HOFFMAN AA, HOFFMAN SA, SHUCARD DW: Ruiz, who performed the pertechnetate-protein binding experiments, Cerebrospinal fluid and choroid plexus during immune complex and Nayda Quinones, for much of the technical work required in this disease. Clin Immunol Immunopathol 13:413—425, 1979 study. 19. WOLFSTEIN RS, TANASESCU DE, WAXMAN AD, SIEMSEN JK: Transient brain scan abnormalities in renal dialysis patients. J Nuci Med 17:6—8, 1976 Reprint requests to Dr. J. V. Rivera, Nuclear Medicine Service, 20. MAHUKAR DM, MEYERS L JR, COHEN J, KAMATH RV, DUNEA G: Veterans Administration Medical and Regional Office Center, GPO Electroencephalographic and radionuclide studies in dialysis de- Box 4867, San Juan, Puerto Rico 00936 mentia. Kidney mt 13:306—3 15, 1978