Bone Scintigraphy in Uremie Pulmonary Calcification

P. de Graaf, I. M. Schicht, E. K. J. Pauwels, J. H. M. Souverijn, and J. de Graeff

University Hospital, Leiden, The Netherlands

The value of Tc-99m HEDP bone scintigraphy as a means of detecting uremie

pulmonary calcification was studied in 30 chronic dialysis patients. A high incidenceof currently recognized predisposing factors for met astatic calcification was found andcalcification was recorded at other sites. Scintigraphy was performed after reducingbackground activity by hemodialysis to levels found in normals. From chest imagesand chest-to-spine activity ratios, evidence of pulmonary calcification could be obtainedin only one patient, and subsequent histologie examination revealed extensive calcification. High chest-to-spine activity ratios suggested increased pulmonary radionu-

clide uptake in several other patients, but these findings were not conclusive. Theseresults indicate that uremie pulmonary calcification—which, according to autopsystudies, develops in about 60-75% of dialysis patients—cannot be detected with bone-

seeking radiopharmaceuticals, unless the calcification is severe. This is probably dueto the unusual crystalline and chemical composition of uremie pulmonary calcification.

J NucíMed 20: 201-206, 1979

Metastatic pulmonary calcification, a frequentand potentially lethal complication of chronic renalfailure, is rarely detected before death, because ofthe absence or nonspecificity of the radiographieabnormalities (1-7).

The incidental demonstration of an increased accumulation of bone-seeking radiotracers in thelungs of uremie patients with metastatic calcification (8-75, 32) suggested a practical and relativelyspecific technique for detection of this condition(16).

This was investigated with Tc-99m HEDP scintigraphy in 30 patients on chronic hemodialysis, andthe resulting qualitative and quantitative scinti-graphic data were evaluated.

MATERIALS AND METHODS

Thirty patients (21 males and nine females) onregular hemodialysis were studied. The median agewas 37 yr (range 15-58); the median duration of

Received July 31, 1978; revision accepted Oct. 25, 1978.For reprints contact: P. de Graaf, University Hospital, Dept.

of Nephrology, 2333 AA, Leiden, The Netherlands.

dialysis was 41 mo (range 4-101). The causes ofrenal failure were: chronic glomerulonephritis, 15;chronic pyelonephritis, eight; polycystic renal disease, five; acute tubular necrosis, one; and hemo-lytic-uremic syndrome, one. Disposable parallel-plate dialyzers were used for 27 patients; three patients were dialyzed with a disposable hollow-fiber

FIG. 1. Chest scintigram 2-3 hr after the radionurlide injection without prior hemodialysis.

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TABLECa

(mmol/l)PO4(mmol/l)Mg(mmol/l)Ca/PO4productCa/Mg/PO4

product1.

MEAN PREDIALYSISNormal

values2.25-2.650.81-1.450.65-0.98<3.84<3.76BIOCHEMICALLow16---â„¢VALUES

INNormal137-12530DIALYSISPATIENTSElevated123301825(range)(2.80)(1.57-

3.17)(1.04-1.86)(3.88-8.45)(3.78-11.25)

dialyzer. The dialysate fluid calcium concentrationwas 6 mg/100 ml, magnesium was 1.82 mg/100 ml.All patients received phosphate-binding antacids;seven patients were treated with 0.2 mg dihydro-tachysterol daily. Subtotal parathyroidectomy hadbeen performed in five patients. Histologie evidence of renal osteodystrophy was demonstrated inthe iliac-crest bone biopsies of all patients.

The currently recognized predisposing factors forextraosseous calcification, such as the Ca/PO4 andCa/Mg/PO4 products (18,22), were calculated fromthe mean of five consecutive predialysis values.Pyrophosphate (19,20) was determined in predialysis serum according to the method of Solomonsand Styner (23).

Chest roentgenograms and arterial samples forblood gas analysis were obtained immediately afterdialysis to avoid the influence of excessive pulmonary fluid. Metastatic calcification at nonvisceralsites was evaluated by means of radiographs, ocularslit lamp examination, and histologie examinationof skin biopsies.

Before scintigraphy, elevated soft-tissue radio-nuclide levels were reduced by hemodialysis to normal levels as previously reported (24). This isnecessary because raised soft-tissue levels, causedby lack of renal excretion of the radiotracer, occurin patients without markedly elevated skeletal ra-dionuclide uptake, which may complicate the interpretation of radiotracers uptake by pulmonary calcification. An example of such a chest image, taken2-3 hr after the tracer injection but without priorhemodialysis, is shown in Fig. 1.

After i.v. injection of 10 mCi Tc-99m HEDP per70 kg body weight, all patients were dialyzed fornearly 5 hr. Scintigraphy was performed after 6 hrwith a large-field gamma camera provided with twocount sealers and the capacity to register counts inselected regions of interest. Standardized chest images were obtained and quantitative data were collected in the regions of the spine and chest by registering count rates. The activity rate registered wasdose-corrected for 10 mCi Tc-99m and expressedas kilocounts per second (kC/sec). Chest-to-spineactivity ratios were calculated for all patients andeight normal controls.

RESULTS

The biochemical data are summarized in Table 1.The Ca/PO4 and Ca/Mg/PO4 products were elevated, respectively, in 60% and 83% of the patients.Serum magnesium was elevated in all cases. Themean serum pyrophosphate (PPi) level in 18 normals was 3.41 ¿imol/1,as reported by Russell et al(26), with a range of < 1-13 /umol/1. The mean PPilevel in the patients was 4.52 /umol/1, and it too

FIG. 2. Markedly increased pulmonary radionuclide uptakedue to metastatic calcification.

FIG. 3. Chest radiograph of the patient with pulmonary calcification, showing marked interstitial abnormalities.

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varied markedly (27) within a range of 1-13.5 /xmol/1. In 13 patients (43%) and five normals (23%), PPiexceeded the mean normal value. However, sincemarked variations occurred in both groups, thesefindings are not conclusive.

Nonvisceral calcification was demonstrated inthe eyes (63%), arteries (33%), and at periarticularsites (23%). Cutaneous calcification could not bedemonstrated.

Chest films showed calcified upper airways intwo patients, without interstitial abnormalities. Anonspecific fine reticular pattern, suggestive of pulmonary calcification, was found in three patientsbut was marked in only one. The latter also hadmarked hypoxemia. Postdialysis arterial blood gasstudies revealed low PO2 values (normal 80-100mm Hg) in only two other patients. One of thesepatients had pulmonary emphysema and the otherpulmonary congestion.

With scintigraphy, increased pulmonary radion-uclide uptake (Fig. 2) was noted only in the patientwith marked radiographie interstitial pulmonary abnormalities (Fig. 3). An open lung biopsy subsequently yielded histologie proof of extensive pulmonary calcification (Fig. 4). Pulmonary functiontests showed restrictive and diffusion ventilatorydefects and lung scintigraphy with Tc-99m ma-croaggregates revealed multiple small perfusion defects. Marked ocular, arterial and periarticular calcification was present as well.

Quantitative data for the spine and chest regionsare shown in Fig. 5, and the chest-to-spine activityratios in Fig. 6. The mean chest-to-spine ratio fornormals was 2.08 (range 1.69-2.37) and for the patients 2.71 (range 1.61-4.68). In 66% of the patientsthese ratios exceeded the upper limits found in normals. No relationship to the Ca/PO4 or Ca/Mg/PO4products or to serum pyrophosphate could be established. Although these ratios are also dependenton the degree of skeletal involvement in renal os-teodystrophy, the highest ratios were found in thethree patients with radiologie abnormalities suggestive of pulmonary calcification. The highest ratiowas that of the patient with proven pulmonary calcification (Fig. 6). In the two other patients withhigh activity ratios, the radiologie interstitial abnormalities disappeared after renal transplantation.Scintigraphy, repeated 6 and 12 mo later, showeda decrease in these ratios from 3.84 and 3.92 to 2.26and 1.74, respectively.

DISCUSSION

In the present study, pulmonary calcification wasfound by scintigraphy and subsequently confirmedhistologically in only one patient. Elevated chest-

if, •

•''•

FIG. 4. Section from lung biopsy showing marked, scatteredcalcific deposits in thickened alveolar walls (von Kossa, x100). (33% photographic reduction)

to-spine ratios were found in 66% of the 30 patients,the highest being those of the three patients withradiologie abnormalities suggesting pulmonary calcification. These findings suggest that increasedpulmonary radionuclide uptake, although not ap-

. -

2.8-

2.2 -

2.0

Oo

U

1.0

OS

0.2

i%l

tA

r•patientsa normals

CHEST SPINE

FIG. 5. Quantitative data for regions of spine and chest,expressed as kilocounts/sec, normalized to 10-mCi dose ofTc-99m HEDP. (ir Proven pulmonary calcification.)

Volume 20, Number 3 203

DE GRAAF, SCHICHT, PAUWELS, SOUVERIJN, AND DE GRAEFF

5 -

u01Ul

>>I-u

Lu

Etn

cnLUXuo

§

3-

2-

1 -

fcBa

B

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i*

NORMALS PATIENTS

FIG. 6. Chest-to-spine activity ratios in eight normals and30 patients. (•&Proven pulmonary calcification. «—Radiograph suggestive of pulmonary calcification without visiblyincreased pulmonary radionuclide uptake.)

parent in the scan, may have contributed to theseelevated ratios. However, since the presence ofpulmonary calcification could not be proven histo-logically in the remaining patients with elevatedratios, this evidence cannot be considered conclusive.

Pulmonary calcification is known from autopsystudies to occur frequently in chronic renal failure.Conger et al. (/) reported an incidence of 60%.Kuzela et al. (2) found an incidence of 75%, andcalcification was severe in approximately 50% ofthese cases. Nevertheless, radiographie abnormalities are often absent or nonspecific, or may mimicpulmonary edema or pneumonic infiltrates in severecases (1-7). The fact that radiographie abnormalities are often absent can probably be attributed tothe smaller size of the crystals in uremie pulmonarycalcification, which evokes a less intense tissue reaction than larger crystals such as hydroxyapatite(//,/*).

In uremia, nonvisceral calcification is hydroxyapatite, which has a crystal structure and chemicalcomposition similar to that of uremie bone (17,18).Pulmonary calcification due to other causes in non-uremic patients has also been shown to be hydroxyapatite (18,19). However, uremie pulmonary calcification is not hydroxyapatite but an amorphousor microcrystalline compound with a high magnesium and pyrophosphate content (17,20). Alfrey etal. (20) found extensive pulmonary calcification inall uremie patients with a markedly elevated magnesium and pyrophosphate content in bone andlung, whereas these concentrations were withinnormal ranges in uremie patients without pulmonary calcification. They suggested that a disturbedmetabolism of magnesium and pyrophosphate—both often being elevated in uremie patients (25,-27)—might be of importance in the pathogenesis ofuremie pulmonary calcification (18,20). Furthermore, they noted that visceral calcification usuallydeveloped in patients who were free of nonvisceralcalcification, suggesting different pathogenic mechanisms for these two types of metastatic calcification in uremia. Proposed pathogenic factors foruremie pulmonary calcification include a raised Ca/Mg/PO4 product (18) or elevated serum pyrophos-phate and/or magnesium levels leading to deposition of a magnesium-pyrophosphate complex in softtissue (¡9,20).This would presumably inhibit formation of hydroxyapatite crystals at visceral sites.However, current theories fail to explain fully whyhydroxyapatite crystal formation is not inhibited atnonvisceral sites, since these two types of calcification are also known to coexist (2), as demonstrated in our patient with pulmonary calcification.

In the present study, serum magnesium was elevated in all patients, serum pyrophosphate in 13patients (43%) and the Ca/Mg/PO4 product was increased in 83% of the patients. This product washighest in the patient with proven pulmonary calcification. However, despite the high incidence ofthe currently recognized factors predisposing touremie pulmonary calcification, and the known highincidence as indicated by autopsy studies, pulmonary calcification could not be demonstrated withbone-seeking radiotracers in the remaining patients.

Technetium-99m-labeled phosphate compoundsare known to bind to hydroxyapatite crystals, probably by a process of chemisorption (28). Less likely,however, is radionuclide binding to amorphous ormicrocrystalline pulmonary calcifiédeposits witha high pyrophosphate content. Conger and Alfrey(27) actually demonstrated diminished uptake of Tc-99m diphosphonates by visceral calcification invitro. Nonvisceral calcification with an apatite cry s

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tal structure absorbed 98% of the radionuclide fromthe bath medium, but visceral amorphous calcification absorbed only 24%. They found no increasein pulmonary radionuclide uptake in ten chronicdialysis patients, although pulmonary calcificationwas demonstrated at autopsy in one case. 01gaard(29) performed bone scintigraphy in 30 chronic dialysis patients and noted an increase in pulmonaryradionuclide uptake in only three. In similar studiesof chronic dialysis patients, Sy (30) and Neyer (31)reported no increased uptake in 14 and 24 patients,respectively. Furthermore, most of the uremie patients with reported increased pulmonary radionuclide uptake had concomitant diseases causing hy-percalcemia (9-14), which could have causedpulmonary hydroxyapatite formation. Only Velen-tzas et al. (33) reported an increase of pulmonaryradionuclide uptake, in the absence of generalizedsoft-tissue activity, in 11 of 22 dialysis patients.This uptake was marked in only two, moderate infive, and minimal in four patients. However, sinceskeletal radiotracer uptake was also graded as minimal in the latter patients, increased soft-tissue activity must have occurred without prior hemodi-alysis. Thus, in the absence of histologie proof ofpulmonary calcification, it is doubtful whether aminimal increase of pulmonary radionuclide uptakeindicates calcification. The moderate or marked increased radionuclide uptake in the lungs and skeleton in six of these patients strongly suggests severepulmonary calcification, which could have beencaused by vitamin D treatment or, as these authorssuggest, could be attributed to the predominance ofthese patients undergoing long-term peritoneal dialysis. The latter is less effective in lowering serumphosphate than hemodialysis, with resultant higherCa/PO4 products, and possibly the removal of theinhibitors of calcification (34).

From this study it appears that bone scintigraphyis not a sensitive technique for detecting uremiepulmonary calcification, except in severe cases.The affinity of bone-seeking radiotracers for uremiepulmonary calcification is apparently less than thatfor hydroxyapatite calcification, as indicated by thedemonstration of diminished uptake in vitro (27).Whether in the absence of clearly visible pulmonaryradionuclide uptake, markedly elevated chest-to-spine ratios are indicative of milder forms of pulmonary calcification could not be confirmed.Hence, accurate diagnosis still depends on histologie examination of lung tissue; but bone-seekingradiopharmaceuticals might prove useful in detecting severe pulmonary calcification, and scintigraphy should be performed in uremie patients withnonspecific chest-film abnormalities and/or markedly disturbed pulmonary function (7).

ACKNOWLEDGMENTS

We thank Mrs. L. H. van Welij for preparing the manuscriptand Mr. F. Fisser for laboratory assistance.

This study was presented in part at the 1978 Annual Meetingof the Society of Nuclear Medicine, Anaheim, California, June27-30.

REFERENCES

/. CONGERJD, HAMMONDWS, ALFREYAC, et al: Pulmonarycalcification in chronic dialysis patients. Clinical and pathologic studies. Ann Int Med 83: 330-336, 1975

2. KUZELADC, HUFFER WE, CONGERJD, et al: Soft tissuecalcification in chronic dialysis patients. Am J Palhol 86:403-424, 1977

3. DAVIDSON RC, PENDRAS JP: Calcium-related cardio-respiratory death in chronic hemodialysis. Trans Am SocArt Int Organs 13: 36-40, 1967

4. McLACHLAN MSF, WALLACE M, SENEVIRATNE C: Pulmonary calcification in renal failure. Report of three cases.Br J Radial 41: 99-106, 1968

5. MOOTZ JR, SAGEL SS, ROBERTS TH: Roentgenographicmanifestations of pulmonary calcification. A rare cause ofrespiratory failure in chronic renal disease. Radiology 107:55-60, 1973

6. KAI.TREIDER HB, BAUM GL, BOGATY G, et al: So-called"metastatic" calcification of the lung. Am J Med 46: 188-

196, 19697. NEFF M, YALCIN S, GUPTA S, et al: Extensive metastatic

calcification of the lung in an azotemic patient. Am J Med56: 103-109, 1974

8. HOLMESRA: Detection of diffuse metastatic pulmonary calcification with radiostrontium. J NucI Med 11: 327-328, 1970(abst)

9. GRAMESGM, SAUSERDD, JANSENC, et al: Radionuclidedetection of diffuse interstitial pulmonary calcification.JAMA 230: 992-995, 1974

10. MCLAUGHLIN AF: Uptake of 99mTc bone-scanning agentby lungs with metastatic calcification. J NucíMed 16: 322-323, 1975

//. RICHARDSAG: Metastatic calcification detected throughscanning with ""Tc-polyphosphate. J NucíMed 15: 1057-

1060, 197412. MOINUDDINM, ROCKETTJF, WEBER A: Scanning for pul

monary calcification. Ann Ini Med 84: 224-225, 197613. RICHARDSAG: Radionuclide detection of metastatic calci

fication. JAMA 231: 1339, 197514. ROSENTHALDI, CHANDLER HL, Azizi F, et al: Uptake of

bone imaging agents by diffuse pulmonary metastatic calcification. Am J Roentgenol 129: 871-874, 1977

15. DAVIS BA, POULOSEKP, REBA RC: Scanning for uremiepulmonary calcifications. Ann Ini Med 85: 132, 1976

16. HOLMES RA: Diffuse interstitial pulmonary calcification.JAMA 230: 1018-1019, 1974

17. LEÛEROSRZ, CONTIGUGLIASR, ALFREY AC: Pathologicalcalcifications associated with uremia. Two types of calciumphosphate deposits. Calcif Tissue Res 13: 173-185, 1973

18. CONTIGUGLIASR, ALFREY AC, MILLER NL, et al: Natureof soft tissue calcification in uremia. Kidney Int 4: 229-235,1973

19. ALFREY AC, SOLOMONSCC, CIRICILLOJ, et al: Extraos-seous calcification. Evidence for abnormal pyrophosphatemetabolism in uremia. J Clin invest 57: 692-699, 1976

20. ALFREY AC, SOLOMONSCC: Bone pyrophosphate in uremiaand its association with extraosseous calcification. J ClinInvest 57, 700-705, 1976

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21. CONGERJD, ALFREY AC: In comment: Letter to the editor. pathological calcification in vivo. Science 165: 1264-1266,Reply. Ann Int Med 84: 224-225, 1976 1969

22. PARFITT AM: Soft tissue calcification in uremia. Arch Int 29- OLGAARD K, HEERFORDTJ, MADSEN S: Scintigraphic skel-Med 124: 544-556, 1969 eta' changes in uremie patients on regular hemodialysis.

23. SOLOMONSCC, STYNER J: Osteogenesis imperfecta: Effect Nephron 17: 325-334, 1976of magnesium administration on pyrophosphate metabolism. 30' SY WM> MlTTALAK: Bone scan in chronic dia|ysis PatientsCale Tissue Res 3" 318-326 1969 w evidence of secondary hyperparathyroidism and renal

osteodystrophy. Br J Radial 48: 878-884, 197524. DE GRAAF P, SCHICHT IM, PAUWELS EKJ et al: Bone 3¡ NEYER U, MÄHRÜ,ELLPJ.et al: Die Knochenszintigraphie

scintigraphy in renal osteodystrophy. J NucíMed: 1289- jn der diagnostik der renalen Ostéopathie.Dtsch Med Wschr1296, 1978 103. 45i_455j i978

25. CONTIGUGLIASR, ALFREY AC, MILLER N, et al: Total- 32. DEVACAANTHAN K, YAP AU, CHAYES Z, et al: Pulmonarybody magnesium excess in chronic renal failure. Lancet 1: calcification in chronic renal failure: Use of diphosphonate1300-1302, 1972 scintiscan as a diagnostic tool. Clin Nephrol 6: 488-491,

26. RUSSELL RGG, BISAZ S, DONATH A, et al: Inorganic py- 1976rophosphate in plasma of normal persons and in patients 33. VELENTZASC, MEINDOKH, OREOPOULOSDG, et al: De-with hypophosphatasia, Osteogenesis imperfecta, and other tection and pathogenesis of visceral calcification in dialysisdisorders of bone. J Clin Invest 50: 961-969, 1971 patients and patients with malignant disease. Can Med

27. DAVID DS, SARAI S, GRANDA J, et al: Role of pyrophos- Assoc J 118: 45-50, 1978phate in renal osteodystrophy. Trans Am Soc Art Int Organs 34. OREOPOULOSDG, PITEL S, HUSDANH, et al: Contrasting19: 440-445, 1973 effect of hemodialysis and peritoneal dialysis on the inhibi

ts. FRANCISMD, RUSSELLRGG, FLEISH H: Diphosphonates tion of in vitro calcification by uremie serum. Can Medinhibit formation of calcium phophate crystals in vitro and Assoc J 110: 43-47, 1974

4th ANNUAL WESTERN REGIONAL MEETINGTHE SOCIETY OF NUCLEAR MEDICINE

October 18-21, 1979 Monterey Conference Center and Doubletree Inn Monterey, California

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ticipate. The program will be structured to permit the presentation of papers from all areas of interest in thespecialty of nuclear medicine. Abstracts submitted by technologists are encouraged and will be presented atthe scientific program. Abstracts for the scientific program will be printed in the program booklet and willbe available to all registrants at the meeting.

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