Power Doppler Imaging of Acute RenalTransplant Rejection

Manrita K. Sidhu, MD,1 Sangeeta Gambhir, MD,2 R. Brooke Jeffrey, Jr., MD,2 F. Graham Sommer, MD,2

King C. P. Li, MD,2 Nancy R. Krieger, MD,3 Edward J. Alfrey, MD,3 John D. Scandling, MD4

1 Department of Diagnostic Imaging, Children’s Hospital Oakland, 747 Fifty-second Street,Oakland, California 940692 Department of Diagnostic Radiology, Stanford University Medical Center, 300 Pasteur Drive,Stanford, California 943053 Department of General Surgery, Stanford University Medical Center, 300 Pasteur Drive,Stanford, California 943054 Department of Transplant Nephrology, Stanford University Medical Center, 300 Pasteur Drive,Stanford, California 94305

Received 12 June 1998; accepted 17 November 1998

ABSTRACT: Purpose. We evaluated the usefulness ofpower Doppler imaging (PDI) in diagnosing acute re-nal-transplant rejection.

Methods. Twenty-eight patients underwent 33 re-nal-transplant biopsies for suspected acute rejection.Patterns of renal parenchymal vascularity revealed byPDI in patients with abnormal biopsy results werecompared with patterns in a group who had normalbiopsy results. PDI examinations were reviewed ret-rospectively by 2 independent radiologists who hadno knowledge of the biopsy results. A PDI diagnosis ofacute rejection required marked vascular pruning inboth the cortex and medulla. PDI results then werecompared with transplant-biopsy results.

Results. The sensitivity and specificity of PDI fordiagnosing acute renal-transplant rejection were 40%and 100%, respectively. None of the patients withnegative biopsy results had PDI abnormalities. Thenegative predictive value of PDI was 33%, and thepositive predictive value was 100%.

Conclusions. In our study, an abnormal sonogramwas highly predictive of acute transplant rejection.However, a normal sonogram did not exclude the pos-sibility of rejection. © 1999 John Wiley & Sons, Inc.J Clin Ultrasound 27:171–175, 1999.

Keywords: kidney, transplantation; Doppler ultraso-nography

Identifying the cause of acute renal-transplantdysfunction can be a diagnostic challenge. The

pathologic considerations are broad and includetransplant rejection, acute tubular necrosis, uri-nary tract obstruction or infection, and toxiceffects of cyclosporine or other drugs. Many po-tential causes of transplant dysfunction are cur-rently impossible to distinguish without biopsy.Doppler measurements of resistance or pulsatil-ity indices are not yet sufficiently accurate to ob-viate transplant biopsy.1–4 The development ofpower Doppler imaging (PDI) affords significantlyincreased sensitivity for detecting renal paren-chymal perfusion. We hypothesized that renal-transplant rejection might be accompanied by asignificant decrease in allograft perfusion. To testthis hypothesis, we retrospectively evaluated thepatterns of renal allograft perfusion detected byPDI in patients with biopsy proven acute renal-transplant rejection and in patients with renaltransplants who had normal biopsy results.

PATIENTS AND METHODS

From May 1994 to March 1995 and from July toOctober 1996, all renal biopsies in renal-transplant patients were preceded (within 1 day)by PDI examination. A total of 33 renal biopsieswere performed in 28 patients. For this retrospec-tive study, this group was divided according to

Correspondence to: R. B. Jeffrey, Jr.

© 1999 John Wiley & Sons, Inc. CCC 0091-2751/99/040171-05

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biopsy results as follows. The study group com-prised 22 patients in whom a pathologic abnor-mality was found at biopsy. This group consistedof 13 men and 9 women ranging in age from 24 to69 years (mean, 38 years). The comparison groupcomprised 6 patients for whom biopsy resultswere negative. This group consisted of 4 men and2 women ranging in age from 33 to 63 years(mean, 45 years).

Thirty-two PDI examinations were performedwith an XP-128 ultrasound scanner (Acuson,Mountain View, CA); 1 was performed with anATL-HDI Mark 9 scanner (Advanced TechnologyLaboratories, Bothell, WA). A curved 5-MHz or7–4-MHz transducer was used for all patients.Settings for PDI on the Acuson unit included the“low flow” application program, gain of 35 dB,power output of 500, 2.5-mm gate, wall filter of 2(low to medium volume), velocity scale of 0.05 cm/second, color map E5, and color–gray-scale prior-ity mix of 4. The gain setting was adjusted to justbelow noise level. Settings for PDI on the ATLunit included a wall filter of 100 Hz, pulse-repetition frequency of 1,500 Hz, high sensitivity,and persistence level of 6; color gain was adjustedto just below noise level.

All PDI examinations were reviewed retrospec-tively by 2 radiologists working independentlywithout knowledge of biopsy results. Longitudi-nal images of the transplanted kidney were usedfor analysis. Each examination was analyzed for

the presence or absence of markedly decreasedparenchymal flow. Normal flow was diagnosedwhen uniform cortical flow was present (Figure1). Abnormal flow or vascular pruning was diag-nosed when a uniform pattern of decreased flowwas seen in both the cortex and medulla (Figure2). Mild cortical hypoperfusion was not classifiedas abnormal in this study (Figure 3). Discrepan-cies in sonographic diagnosis were resolved byconsensus between the reviewers, who remainedunaware of the biopsy or clinical results.

Biopsy results were evaluated by members ofthe pathology department who had no knowledgeof the PDI results. The biopsy diagnoses consistedof the following: rejection, acute tubular necrosis,FK506 toxicity, cyclosporine toxicity, resolvingpreservation injury, and Epstein-Barr virus infec-tion. Because neither the type (“cellular” versus“vascular”) nor the severity of rejection was re-ported consistently, we did not attempt to sub-classify the types of acute rejection.

We then compared the independently scoredPDI findings with the pathology results and com-pared results from the abnormal-biopsy groupwith those of the normal-biopsy control group todetermine numbers of true positives, true nega-tives, false positives, and false negatives. Sensi-tivity, specificity, and positive and negative pre-dictive values were calculated with the followingstandard formulas and expressed as percentages.Sensitivity was defined as: [true positives/(true

FIGURE 1. Longitudinal power Doppler sonogram of a normal transplanted kidney shows uniform parenchy-mal “blush.”

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positives + false negatives)] × 100. Specificity wasdefined as: [true negatives/(true negatives + falsepositives)] × 100. Positive predictive value wascalculated as: [true positives/(true positives +false positives)] × 100. Negative predictive valuewas calculated as: [true negatives /(true negatives+ false negatives)] × 100.

RESULTS

Of the 33 biopsy samples examined, 6 (from 6 pa-tients) had no definite pathologic abnormality (ie,biopsy findings were interpreted as “normal” or“mild nonspecific changes”). The remaining 27 bi-opsy samples (from 22 patients) showed 20 cases

FIGURE 2. Longitudinal power Doppler sonogram of a transplanted kidney in a patient with biopsy-provenacute rejection shows severe vascular pruning of the cortex and medulla.

FIGURE 3. Longitudinal power Doppler sonogram of a transplanted kidney shows selective cortical hypoper-fusion. Flow to the cortex is decreased, but perfusion to the medulla is normal. These findings were notconsidered sufficient for a PDI diagnosis of rejection. Biopsy, however, revealed acute rejection. Arrowsindicate margin of cortex.

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of acute rejection (with or without other patholog-ic findings), 3 cases of chronic rejection, 3 cases ofcyclosporine toxicity, and 1 case of resolving pres-ervation injury. Of the 20 cases of pathologicallyproven acute transplant rejection, 3 cases alsoshowed chronic rejection, 1 also showed FK506toxicity, 2 showed Epstein-Barr virus infection, 1showed cyclosporine toxicity, and 1 showed acutetubular necrosis.

In the 20 cases of pathologically diagnosedacute transplant rejection, PDI revealed a patternconsistent with vascular pruning in 8 and no ab-normality in 12. None of the 6 cases in which bi-opsy results were negative demonstrated vascu-lar pruning. Therefore, the sensitivity andspecificity of PDI for diagnosing acute rejectionwere 40% and 100%, respectively. The negativeand positive predictive values were 33% and100%. The numbers of patients who had abnor-mal biopsy results but not acute rejection weretoo small for analysis. However, 2 of the 3 pa-tients who had cyclosporine toxicity had vascularpruning on PDI, and the other had normal PDIresults. One of the 3 cases with pathologic evi-dence of chronic rejection had vascular pruningon PDI. There was interobserver disagreementregarding the presence of pruning on PDI in 6cases, resulting in an overall interobserver agree-ment rate of 82%.

DISCUSSION

The Banff international classification system forhistologic diagnosis of acute renal allograft rejec-tion recognizes intimal arteritis as one of the ma-jor pathologic findings of cellular (interstitial) re-jection.5 Biopsy studies have demonstrated thatthis finding occurs in both the cortex and medullaof the rejected allografts.6 The rarer acute vascu-lar rejection syndrome is characterized by capil-lary thrombi and fibrinoid changes in glomerularand arterial walls.5 These pathologic changesform the basis of our hypothesis that decreasedrenal perfusion identified by PDI may be a usefulindicator of acute renal-transplant rejection.

The PDI technique involves color-encoding theentire integrated Doppler power spectrum ratherthan just the mean frequency shift, as does con-ventional color Doppler imaging.7–9 Thus, PDI ismore sensitive to the depiction of blood flow and ismuch less angle-dependent than is conventionalDoppler imaging.7 PDI has been shown to corre-late with experimentally induced changes in per-fusion in the kidneys in animals8 and in othertissues in humans.9 PDI has also been used toestimate the fraction of moving blood in tissue.10

Bude et al11 have demonstrated that PDI allowsvisualization of small blood vessels in the renalcortex; the blood flow in the cortical vessels sum-mated into a diffuse cortical “blush” in 18 of 20kidneys in that study. More recently, Martinoli etal12 visualized the interlobular vasculature in re-nal transplants.12 In that study, perfusion at theinterlobular level was diffusely decreased in 2 pa-tients with acute rejection.

In our study, PDI was less sensitive than bi-opsy for the detection of acute renal-transplantrejection. Severe parenchymal hypoperfusion orvascular pruning was present in only 40% of pa-tients with biopsy-proven acute rejection. Weused a purely qualitative assessment of the pat-tern of renal allograft perfusion as depicted byPDI but chose a strict criterion for the diagnosisof acute rejection to minimize interobserver error.Subtle changes in only cortical or only medullaryperfusion (Figure 3), for example, were not con-sidered a useful criterion for diagnosing acute al-lograft rejection.

Another factor that complicates assessments ofthe ability of PDI to detect acute rejection is thefrequent coexistence of other pathologic condi-tions, as was seen in our study and those of oth-ers.13 From our investigation of 33 biopsies, weconclude that PDI is not accurate enough to re-place biopsy in the detection of acute transplantrejection, a conclusion also reached by others.13,14

However, abnormal PDI results are suggestive ofacute transplant rejection. Further investigationmay be necessary to evaluate the potential con-founding effects of other pathologic entities suchas cyclosporine toxicity.

ACKNOWLEDGMENTS

We thank Diane Orluck, RDMS, RVT, lead sonog-rapher; Jacqueline Bailey, RDMS, staff sonogra-pher; and Kevin Murphy and Derick Yih, admin-istrative associates.

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