radiology in the diagnosis of renal rejection

Clin. RadioL (1970) 21, 109-118

RADIOLOGY IN THE DIAGNOSIS OF RENAL REJECTION

ERIC SAMUEL

From the Department of Diagnostic Radiology, University of Edinburgh

An analysis is presented of 35 patients who received renal transplants in the Edinburgh Unit of Professor Sir Michael Woodruff. The radiological aspects of renal rejection are emphasised, with particular reference to vascular changes. The value of intravenous pyelography, tomography and arteriography is discussed in relation to the investigation of failing renal function following transplantation. Pulmonary changes may be seen during renal rejection and the pathogenesis and radiological appearance are briefly discussed.

THE surgical problems associated with renal transplantation have been largely overcome, but dominating the successful outcome in any individual case is the problem of rejection of the transplant. The sooner treatment can be instituted, the more likely is rejection to be contained; consequently any method that can be used to detect or confirm rejection warrants careful consideration. This paper is presented to illustrate the Edinburgh findings in some of the cases of renal rejection investigated by radiological methods. It is not our routine to perform arteriography on .every case suspected of renal rejection, as the clinicians concerned with the management of the case prefer to institute immuno- suppressive therapy on the assumption that rejection is present if certain symptoms and signs appear.

Acute rejection of the transplanted kidney appears to occur at two main time periods; first occurring in the early post-operative period (7 days) and the second at the 32-37th day post-operatively. These acute rejection episodes are, according to many authorities, probably episodes in a continuing process of chronic rejection.

The basic pathology of rejection is not fully understood but it appears that antibody sensitised

lymph cells attack the vascular endothelium of the transplant which ultimately leads to thrombosis and vessel obstruction. Initially damage to the endothelium results in an increased permeability of the vessel wall with passage of the cells into the interstitial tissues.

The sensitised lymphocytes arise from the circulating lymphocytes: when the renal transplant is involved, both the glomerulus and tubules are attacked by the rejection process.

The tubules appear to be particularly vulnerable and the first histological change in the rejection process appears in this portion of the kidney (Fig. 1). Swelling of the interstitial tissue between the tubules results in enlargement of the pyramids and these pathological changes are reflected in the radiological findings.

Meanwhile the glomerulus becomes infiltrated with round cells and the lumens of the intra-lobular vessels are reduced by proliferation of the endothelium and thrombus, and result in ischaemia of segments of the kidney.

The tubular damage is also probably part ischaemic. Initially the glomerulus is spared as the glomerular arteries represent a high pressure zone

FIG. 1 FIG. 2 FIG. 1--Section of kidney (H. ;& E. × 50) showing the thickened endothelial wall of a middle sized renal vessel with almost complete occlusion of the vessel lumen. The haemorrhage into the tissues can be seen in the top left hand corner of the illustration. Fro. 2--Section of kidney (H. & E. × 50) showing some features of rejection. In the top left hand corner the tubules are fairly normal with a slight increase in interstitial

tissue and fragmentation of the tubules.

109

110 C L I N I C A L R A D I O L O G Y

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112 C L I N I C A L R A D I O L O G Y

as compared with a low pressure zone in the vessels in the tubule region which is more susceptible to ischaemic change (Fig. 2).

Thirty-five renal transplants have been carried out by Professor Sir Michael Woodruff and his team at Edinburgh during the years 1960-1968. The figures of rejection have been published (1969) and are shown in Tables A, B, C and D.

Arteriography has not been carried out in all these cases as clinical judgement now considers that the prospect of control of rejection is best achieved by increasing the dose of immuno- suppressive drugs and without recourse to investigation.

The features listed below were noted in cases investigated.

CLINICAL AND RADIOLOGICAL FEATURES The clinical features of rejection are those of

malaise and generally feeling unwell, coupled with fever and associated with a fall in the urinary output. These symptoms are, however, in no way specific.

The biochemical features equally are non-specific and consist of a raised blood urea, non-protein nitrogen, and increased blood creatinine. A marked decrease in the creatinine clearance ratio indicates the onset of renal failure.

Some authorities have adopted a pragmatic approach to the diagnosis of rejection by implying that if radioisotope tests indicate that perfusion of the kidney is occurring, a decrease in renal urinary

output must imply renal rejection. However, the clinical and biochemical features of rejection can be produced by other causes such as renal artery thrombosis, renal vein thrombosis or obstructive uropathy consequent on mechanical damage to the ureter and a more detailed investigation is there- fore probably warranted. 1. OBSTRUCTIVE UROPATHY

Obstruction to the ureter most frequently develops at the site of implantation into the bladder. Sloughing of the lower end of the ureter may occur if the vascular supply to the ureter is impaired, These changes result in a breakdown of the anastomosis with the occurrence of fistula forma- tion and ureteric obstruction.

The value of intravenous pyelography in determining the site of obstruction largely depends on the function of the kidney as often the relatively poor concentration of contrast medium together with the overlapping gas shadows often impair the delineation of the ureter and the site of obstruction. Tomographic studies are invaluable in demonstrating the outline of the kidney and will often show the lower end of the ureter.

The value of tomography and intravenous pyelography in elucidating the cause of diminished renal function is shown in Figs. 3-5. The patient, a young male aged 27, had received a cadaver transplant seven weeks before but had noticed a fall off in his urinary output together with some dis- charge of urine from the scar in the right iliac fossa.

Fxo. 3 Fro. 4

R A D I O L O G Y IN THE D I A G N O S I S OF RENAL R E J E C T I O N 113

FIG. 5 FIG. 6 FIG. 3--Obstructive uropathy after transplant showing the 7-minute intravenous pyelogram with good function. FIGS. 4 & 5--Tomograms showing the dilated and redundant ureter with a cavity at the lower end- Improved demonstration by tomography. The enlarged shadow of the kidney normally seen in its new position is seen. FIG. 5--The bladder is emptied. No reflux. Fro. 6--The skin fistula injected with

contrast medium.

Intravenous pyelography showed distension of the pelvis and calyces and also of the ureter as far as the bladder. A cavity filled with contrast just lateral to the bladder wall connected with the distended ureter. Tomography shows the outline of the kidney and also the pelvis and calyces more clearly by blurring the overlying gas shadows.

A sinogram was performed through the fistula at the lower end of the wound and it was shown to arise from the obstructed ureter but not connected to the bladder (Fig. 6).

A retrograde pyelogram may be a more rapid method of demonstrating the patency of the ureter when there is a diminished output from a transplanted kidney.

In this series only a single case of ureteric sloughing was noted. 2. RENAL ARTERY OBSTRUCTION

Obstruction of the renal artery at the site of anastomosis as a sequel of thrombotic disease may also occur after transplantation and may result in a syndrome mimicking renal rejection.

Some degree of arterial narrowing invariably occurs at the site of arterial anastomosis and can be demonstrated in the arteriogram.

Brice, Dowsett and Lowe 0964) noted that in the carotid artery, significant decrease in flow did not occur until 90 ~ of the lumen of the vessel is lost.

Whether these findings can be applied to the renal vessels is not clear and furthermore, whether smaller degrees of arterial narrowing increase the possible risk of rejection. The narrowing of the vessel at the site of anastomosis may predispose to ischaemic change as tubular changes of ischaemic origin to a certain degree inevitably occur in the transplanted cadaver kidney, and these changes must always be assessed in relation to the development of rejection changes.

Our original method of catheterisation of the opposite femoral artery and passing the catheter to the aortic bifurcation has been abandoned as the contrast obtained is not equal to that when the homolateral vessel is used. No untoward sequelae have been met with either technique. Selective catheterisation is not employed. A short Longwell catheter is introduced by percutaneous puncture of the right femoral artery and introduced to approximately 5 cm. above the anticipated site of anastomosis, namely to the upper part of the common iliac artery. Twenty ml. of contrast medium are introduced by hand injection and 3 or 4 films per second are exposed on a rapid film changer.

Oblique views of the kidney may be necessary to demonstrate the site of the arterial anastomosis as the anastomosis may be projected over the paren

II# CLINICAL RADIOLOGY

FIG. 7 FIG. 8 FIG. 7--View of right kidney transplant showing narrowing of the vessel at the site of anastomosis to the internal iliac artery. The degree of narrowing does not appear to be significant. FI6. 8--Localised view

of the narrowed area overlying the common iliac artery. Oblique views should be used.

vessel. Some degree of narrowing is always present at the site of arterial anastomosis but if any dilata- tion of the renal artery is present beyond the anastomosis, then significant narrowing of the artery is considered to be present (Figs. 7 and 8).

One case of renal artery stenosis occurred in this series: this ultimately resulted in a loss of the transplanted kidney. Clinically it was considered that rejection was occurring. Arteriography was unfortunately not carried out and a fatal outcome occurred as the result of renal failure. At autopsy a "diaphragm" was found almost completely obliterating the lumen of the transplanted renal artery. It was thought that this membrane had developed in association with some new type of suture material used in the arterial anastomosis. The arterial complications in this series are shown in Table C. 3. RENAL VEIN THROMBOSIS

Thrombosis of the smaller intra-renal veins have been reported in the rejection phenomenon (Macdonald, 1968), but a major renal vein thrombosis may develop and cause loss of the graft.

The clinical findings of heavy proteinuria associated with a diminished renal output is strong evidence of a renal vein thrombosis.

Retrograde catheterisation of the common iliac vein and a forced injection during a Valsalva manoeuvre will often fill the anastomosed vein. Whilst filling of the anastomosed vein is positive evidence of its patency, non-filling presents a greater problem in diagnosis as technical factors and non-obstruction may account for the non-filling.

Ellis (1969) reports such a case where the veno- gram showed non-filling of the renal vein which was interpreted as renal vein thrombosis. However, at operation no obstruction was found. Saxton (1969) in discussion of the case considered that streaming might have accounted for the findings and raised the question of undertaking the examina- tion in the prone position.

RENAL REJECTION

Two distinct phases of renal rejection appear to occur, one in the immediate post-operative period (7 days) and a second crisis between the 5th and 6th week.

In the suspected rejection occurring in the immediate post-operative period, arteriography is not undertaken as such cases are treated empirically by increasing the immuno-suppressive therapy. Many authorities consider that some degree of

R A D I O L O G Y IN THE D I A G N O S I S OF R E N A L R E J E C T I O N 1}5

FIG. 10

FIe. 9

chronic rejection inevitably occurs in all cases and the following radiological signs are those when acute crises develop.

As not all cases have been subjected to arteriography, it is not possible to give valid figures as to the frequency of the following findings noted in cases where rejection occurred:

(A) AN INCREASE IN KIDNEY SizE--Swelling of the kidney occurs as a result of an increase in the fluid content of the kidney. The extent of enlargement may be such as to be clinically palpable.

Lesser degrees of renal enlargement may be detected radiologically, but it must be remembered that in its new position a 17 ~ (in loin), 25 9/oo (in bony pelvis) enlargement normally occurs from magnification (Moell, 1961) and this must be taken into account when considering renal size. Fletcher and Lecky (1969) have reported that a 20 9/00 increase in length of the transplanted kidney as compared with the same kidney in the donor probably indicates rejection, whereas an enlargement of less than 20 9/00 in length probably implies that rejection is not occurring.

The difficulties of measuring the soft tissue outline of the transplanted kidney in its new position is increased by the absence of perinephric fat but an intravenous pyelogram will usuall}~i~roduce a su~cient nephrogram phase to allow accurate measurement.

Metallic markers placed on the renal cortex at the time of transplantation, as a means of measuring the renal length, are not wholly accurate

Fic. 11

Fins. 9, 10 & l l - - R e n a l rejection showing a delay in the "run off" of the contrast medium and the persistence of the medium within the arterial tree. Time sequence--Fig. 9--0"5 see., Fig. 10--2"0 see.,

Fig. 11--3'5 sec-

as the metallic clips may not lie at the periphery of the kidney when enlargement occurs and furthermore rotation of the kidney may give a false position of the markers (Fig. 7).

Tomography of the transplanted kidney during the nephrographic phase (Fig. 6 ) i s an accurate and useful means of detecting the renal outline (Fig. 5).

(B) DELAY IN THE VASCULAR RUN OFF.--In cases where established rejection had developed, there was marked delay in the emptying of the main arterial branches and a corresponding slow filling of the intra-renal branches was noted. The smaller peripheral branches filled slowly (Figs. 9, 10, 11) and the whole appearance was that of a tree with a few branches. The smaller vessels, however, did not have the tortuous appearances

I16 C L I N I C A L R A D I O L O G Y

Fro. i2 FIG. 12A showing normal renal arterial pattern and Fro. 12R showing the abnormal renal pattern in a patient

undergoing chronic rejection.

seen in the "withered tree appearance" seen in hypertensive arterial disease affecting the kidney. No beading of the smaller branches was seen but the major interpyramidal branches appeared crowded together (Figs. 12A and 12B). Nilson, Bergentz and Olander (1969) in a series of 203 angiograms performed in cases of renal transplantation found that a delay of more than three seconds in the clearing of contrast medium from

the main vessels indicated rejection. Raphael, Steiner, Shackman and Ware (1969) in contrast, did not consider that the speed of clearance of contrast medium allowed differentiation of rejection from tubular necrosis.

( C ) PYRAMIDAL S W E L L I N G . - - I n the early stages of rejection, there is an alteration in the size of the renal pyramids associated with oedema of those structures.

FIG. 13 FIO. 14 Nephrogrophic phases in normal kidney (FIG. 13) compared with the appearances in rejection (FIG. 14) where

enlargement of the negative shadows of the pyramids can be seen. Arteriographic studies.

R A D I O L O G Y IN THE D I A G N O S I S OF R E N A L R E J E C T I O N 117

NORMAL CORTICO- MEDULLARY RATIO

ABNORMAL

REJECTION/ CORTICO- MEDULLARY RATIO /

FIG. 15--Line drawing to show cortico-naedullary ratio.

The corfico/pyramidal ratio is altered and this narrowing of the cortex is seen in the interpyramidal cortex which is compressed and narrowed. (Figs. 13, 14 and 15). The peripheral cortex may itself not be thinned and the whole kidney itself may be enlarged.

The swelling of the renal pyramids during the nephrographic phase may be recognisable before the arterial changes are seen.

(D) POOR PYELOGRAPHIC EFFECT.--If the rejection process is well established, the transplanted organ may fail to excrete the contrast medium with the result that both pyelogram and nephrogram are poor in radiographic density.

Minimal decreases in density of the nephrogram and pyelogram are difficult to evaluate as the contralateral kidney, being equally affected by the renal condition that required transplantation, does not offer a standard for comparison.

PULMONARY CHANGES ASSOCIATED WITH RENAL REJECTION.--The question of whether the circulating renal antibodies can affect other organs has been much discussed since Rifkind, Starzl, Marchioro, Wadde11, Rowlands and Hill introduced the concept of a "transplant lung" in 1964.

Antibodies circulating in the blood should theoretically affect other organs which have antigenically similar structure. Williams and Hume (1969) have shown that the bronchial epithelium is antigenically similar to the epithelium of the kidney glomerulus (and hence changes might be anticipated in the lung).

Unfortunately attempts to produce these changes in experimental animals have not been successful.

Clinically, the changes of a transplant lung appear with the development of the capillary block syndrome with the changes being detected on respiratory function tests before there are changes in the chest radiograph.

Radiological changes described by Rifkind et al. (1964) have been noted as ill defined pulmonary opaci t ies- these must be distinguished from the patchy pulmonary oedema which may be associated with the underlying renal condition or with infec- tion (Table B).

A pathological report by Tison and Baruzzi (1969) on the findings in the lung of a patient dying f rom pulmonary disease appears to be the only recorded case. The patient, who died on the 51st day after transplant, showed histological appearances in the lung field similar to those shown in hyaline membrane disease. The appearance of pulmonary symptoms or radiological signs should raise the question of renal rejection.

Acknowledgements.--I am indebted to Dr. G. B. Hinde and Dr. Leon Morris for permission to use Figs. 7 and 12A from cases which were under their investigative care.

I am also indebted to Dr. Mary Macdonald of the University of Edinburgh for permission to use Figs. 1 and 2, and especially grateful to Professor Sir Michael Woodruff, Mr. B. No/an and Dr. J. S. Robson for free access to the clinical data of these patients who were under their care.

1118 C L I N I C A L RADIOLOGY

REFERENCES

BRICE, J. G., DowsEvr, D. J. & LOWE, R. D. (1964). The Effects of Constriction of Carotid Blood-flow and Pressure Gradient. Lancet, 1, 84-85.

ELLrS, J. (•969). Personal Communication. FLETCHER, E. W. L. & LECKY, J. W. (1969). The radiological

demonstration of urological complications in renal transplantation. British Journal Radiology, 42, 892-898.

MACDONALD, M. K. (1968). Personal communication. MOELL, M. (1961). Kidney Size and its deviation from normal

in acute renal failure. A radiodiagnostic study. Acta Radiologica Suppl., 206, p. 29, 17, 22.

NILSON, A. E., BERGENTZ, S. E. & OLANDER, R. (Paper presented at the XIIth International Congress of Radiology, Tokyo, October 1969).

RAPHAEL, M. J., STEINER, R. E., SHACKMAN, R. & WARE, R. G. (1969). Post-operative angiography in renal homo- transplantation. British Journal Radiology, 42, 873-885.

RIFKIND, D., STARZL, T. E., MARCHIORO, T. L., WADDELL, W. R., ROWLANDS, D. T. & HILL, R. B. (1964). Transplan- tation Pneumonia, Journal American Medical Association, 189, 808-812.

SAXrON, H. M. (1969). Personal Communication. TISON, V. & BARUZZI, G. (1969). Anatomical Aspects of

Transplant lung (letter, Lancet, 1, 266. WmHAMS, G. M. & HUME, D. M. (1969). Personal Communi-

cation. WOODRUFF, M. F. A., NOLAN, B., ROBSON, J. S. &

MACDONALD, M. K. (1969). Renal Transplantation in Man. Lancet, 1, p. 6-12.

BOOK REVIEW

Clinical Nuclear Medicine. By DOUGLAS MAYNARD. Pp. 280. London: Henry Kimpton, 1969. £5 12s 0d.

This book is a well-written description of the principles underlying established radio-isotope techniques and their clinical uses.

The first chapter is a simplified account of Radio-pharmaceuticals and Instrumentation, but in subsequent chapters the emphasis is on the clinical aspects of nuclear medicine. True to American practice, 'Nuclear Medicine' embraces much more than organ scintigraphy. Thus there are many topics of less interest to the diagnostic radiologist in this country than to the physician. These are mainly metabolic and dynamic studies; all are disarmingly simplified.

Each chapter deals with an organ or system, describing in turn the background, principles, radio-pharmaceuticals used, patient preparation, procedures, clinical indications and results. This format is logical and enables information to be traced easily. Also, exposure doses to the whole body and critical organs are neatly and usefully tabulated in each chapter, but the author points out rightly that those doses are approximations culled from the literature in order to give

the 'order' of the dose rather than its precise measurement. The style is lucid and concise, but a few words like 'phazo- cytized' may jar on some British ears. The index is adequate and accurate. The standard of scan illustration is high, and although the illustrations themselves are small, they are fairly profuse. Illustrations of radiographs, on the other hand, are too infrequent and often disappointing. The author has chosen to write an introduction to the subject rather than a reference book, and within these self-imposed limitations he is unable to discuss many problems in detail. The reader who wants further information will draw heavily on the excellent lists of references at the end of each chapter, bearing the title of the original paper as well as its source, Diagnostic radio- logists will regret the lack of opportunity to discuss the relative merits of other methods of investigation, e.g. in the investigation of renal masses or in placental location. Never- theless the author has achieved his aims (which were a little more modest than the price I) and the book will be welcomed alike by student, resident, trainee and clinician seeking a basic introduction to the principles and clinical application of isotope techniques.

E. RnYs DAVtES

radiology in the diagnosis of renal rejection

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