Renal failure following cardiac transplantation—think of the arteries

Robert Dedi, Graham Woodrow, Aleck M. Brownjohn and John H. Turney

Department of Renal Medicine, Leeds General Infirmary, Leeds, UK

Keywords: cardiac transplantation; renal artery stenosis



   Introduction
 Top
 Introduction
 Cases
 Discussion
 References
 
Following the improved survival of cardiac transplant recipients, attention has been drawn to the long-term complications, including renal dysfunction, resulting in substantial effects on morbidity and mortality [1]. A large body of evidence suggests that the primary cause of renal dysfunction is cyclosporin A (CsA) therapy. However, renal failure is not universal, and seems to bear little relationship to CsA dose or trough levels [1,2], suggesting the presence of other contributing factors.

Atherosclerotic renovascular disease is an increasingly common cause of renal failure in the general population, and is associated with those features that also predict dysfunction after cardiac transplantation. In addition, the histopathological changes found in association with renal-artery stenosis are similar to those presumed to be secondary to CsA toxicity. However, the studies of renal failure following cardiac allografting have not looked for renal-artery disease in sufficient detail to exclude this as a possible cause for the decline in glomerular filtration rate and associated renal morphological abnormalities.

We present four patients who developed renal impairment after receiving cardiac transplants, and were subsequently found to have renovascular disease. We suggest that the cardiac transplant population is at risk of atheromatous renal-artery stenosis, and they should be investigated with accurate imaging techniques before they are presumed to suffer from the effects of CsA.



   Cases
 Top
 Introduction
 Cases
 Discussion
 References
 
Case 1
A 47-year-old man underwent cardiac transplantation in 1990 for ischaemic cardiomyopathy following an extensive myocardial infarction 4 months earlier. He was maintained on azathioprine, prednisolone and CsA. Preoperative renal function was normal with a creatinine of 107 µmol/l. Renal-tract ultrasound scanning demonstrated a small left kidney measuring 9.9 cm in length. Following transplantation the patient developed hypertension that remained difficult to control with three agents, including an angiotensin-converting enzyme inhibitor. Six months after transplant, renal function declined (creatinine 165 µmol/l), but there was no further deterioration over the subsequent 7 years. In 1994 the patient underwent elective abdominal aortic aneurysm repair, and he was continually troubled with intermittent claudication. The patient was admitted in 1998 with evidence of pulmonary and peripheral oedema, elevated blood pressure (210/120 mmHg) and a creatinine of 243 µmol/l. There was a clinical suspicion of renovascular disease, and contrast-enhanced magnetic resonance angiography (CE-MRA) of the renal arteries demonstrated bilateral renal-artery stenosis. Bilateral renal stents were placed, leading to a good diuretic phase, and the creatinine fell rapidly to 179 µmol/l. This level of renal function was maintained for approximately 2 months before gradually deteriorating again. With a creatinine of 380 µmol/l, repeat angiography demonstrated mild re-stenosis of the renal arteries and further stents were placed. No improvement of renal function occurred and a renal biopsy revealed widespread glomerulosclerosis affecting 98% of the glomeruli, interstitial fibrosis, and vascular intimal thickening. Approximately 30 months later the patient began maintenance haemodialysis.

Case 2
A 53-year-old man with a history of peripheral vascular disease underwent cardiac transplantation following an anterior myocardial infarction complicated by bi-ventricular dysfunction. Preoperatively his creatinine was 133 µmol/l, and a renal-tract ultrasound scan was unremarkable. He was maintained on CsA and azathioprine. He developed hypertension, which was well controlled on two agents. Renal function remained normal for 1 year post-transplantation but then steadily deteriorated, thought to be due to a combination of CsA toxicity and possible renovascular disease. Eight years after he had received his transplant, and with a creatinine of approximately 600 µmol/l, the renal vessels were imaged with CE-MRA, which demonstrated an occluded right renal artery and a tight proximal left renal-artery stenosis; this was stented. Following this procedure, renal function deteriorated rapidly, such that the patient required dialysis within 2 weeks. He was maintained on haemodialysis until he died 2 years later.

Case 3
In 1993, a 54-year-old smoker with a history of insulin- treated diabetes mellitus and cerebrovascular disease received a cardiac allograft for ischaemic cardiomyopathy. He had suffered a myocardial infarction 4 years earlier and required coronary artery bypass grafting. Pre-operatively his renal function fluctuated (creatinine 150–230 µmol/l), probably related to diuretic therapy. A renal ultrasound scan did not demonstrate any abnormalities. Following transplantation, maintenance immunosuppression included prednisolone, azathioprine and CsA. His renal function remained impaired but stable, with a creatinine of 225 µmol/l. He developed an episode of acute renal failure following elective repair of an abdominal aortic aneurysm, although this recovered, and his creatinine was 263 µmol/l at the beginning of 1996. The patient then failed to attend any clinic appointments for 1 year, and was then admitted with increasing pulmonary oedema. Renal function had deteriorated markedly (creatinine 803 µmol/l), and he required two sessions of haemodialysis. CE-MRA demonstrated significant bilateral renal-artery stenosis, and the patient underwent successful bilateral renal-artery stenting. The creatinine fell to 562 µmol/l over the next 3 days; however, the patient then died unexpectedly. The post-mortem examination revealed widespread coronary-artery atherosclerosis and cardiomegaly, and renal histological abnormalities included diabetic glomerulosclerosis, arteriosclerosis, and interstitial fibrosis.

Case 4
A 43-year-old man with cardiomyopathy complicated by ventricular dysrhythmias underwent cardiac transplantation. He had a history of excess alcohol consumption, but a cardiac biopsy revealed non-specific changes. There was no evidence of coronary-artery atheroma on coronary angiography. Renal function was normal with a creatinine of 111 µmol/l. Three years after transplantation the patient developed nephrotic syndrome associated with a 24 h urine protein level of 4.24 g. His creatinine was elevated at 222 µmol/l. Renal ultrasound and renal arterial duplex scanning were normal. A renal biopsy revealed widespread global glomerulosclerosis and interstitial fibrosis. Subsequently, renal function continued to decline and he underwent further investigations for renovascular disease. CE-MRA scanning demonstrated a tight right proximal renal-artery stenosis, which was stented. Initial progress was satisfactory with the creatinine improving from 360 to 260 µmol/l over a period of 4 weeks. However, renal function then began to deteriorate rapidly. A renal Doppler ultrasound scan showed no evidence of arterial insufficiency and it was felt that little would be gained by repeat angiography. He was started on dialysis 4 months later and remained on haemodialysis for 9 months before receiving a cadaveric renal transplant. He has remained well over the past 18 months.



   Discussion
 Top
 Introduction
 Cases
 Discussion
 References
 
Cardiac transplant patients are at risk of renal dysfunction after grafting. Up to 20% of patients may develop severe renal dysfunction [2], with 4–8% requiring renal replacement therapy [13], with an adverse effect on patient survival. There is a 60% survival rate at 1 year following the start of dialysis, compared to a 5-year survival of 79% for the cardiac transplant population as a whole [1]. Although the nephrotoxic effect of CsA therapy has received most attention as being responsible for renal impairment, it is apparent that there is little correlation between CsA dose or blood concentration levels and the decline in renal function [1,2,4]. It is therefore necessary to elucidate fully other aetiological factors that contribute toward renal damage.

We have reported four cardiac allograft recipients who developed renal impairment following transplantation and were found to have renal-artery stenosis. Three of our patients demonstrated temporary improvement of renal function following stenting, and it is likely that in these cases arterial insufficiency contributed toward the renal dysfunction. The lack of sustained improvement is not entirely surprising as the renal parenchymal injury often comprises not only ischaemic damage consequent on a haemodynamically significant stenosis, but also intra-renal atheroma, cholesterol embolization, and hypertension. Therefore, the response to revascularization is highly variable [5]. Although the biopsy findings in our cases could be attributed to cyclosporin toxicity [4], very similar renal parenchymal changes are found in association with renal-artery stenosis [6].

We believe that renovascular disease should be readily suspected following cardiac transplantation, as the demographic and co-morbid features of these patients place them at risk. Significant renal vascular lesions are commonly found in patients with coronary-artery disease. The extent of coronary-artery lesions and the presence of congestive cardiac failure are independently associated with significant renal-artery disease [7]. As patients with ischaemic cardiomyopathy represent about 40% of all those receiving a cardiac transplant [8], this group is particularly prone to ischaemic nephropathy and renal dysfunction. This association has been demonstrated [2], although the finding has not been universal [1]. It is also known that after cardiac transplantation, peripheral vascular disease, commonly found in association with renal-arterial disease, occurs 10–15 years earlier than would be expected in the general population [9]. It is possible that immunosuppression accelerates the atherosclerotic process, and patients may develop renal-artery stenosis even in the absence of traditional risk factors. Our patient in Case 4 illustrates the point further. He had no evidence of coronary-artery disease and was relatively young. We have reviewed our population of over 200 patients undergoing contrast magnetic resonance angiography to diagnose renal-artery stenosis, and of 19 patients below the age of 50 years, no other patient had a positive scan (unpublished data).

Although searching for renal-artery stenosis has been advocated [3], there has been no accurate assessment of the renal arteries in any of the relevant literature. Van Gelder et al. [1] investigated those patients progressing to end-stage renal failure with Doppler ultrasound scanning. However, this technique can be an inaccurate diagnostic tool [10], and their findings confirm this—two patients with suspected renal-artery stenosis following duplex scanning subsequently had negative intra-arterial contrast angiograms.

We conclude that renal-artery stenosis should be considered before the assumption is made that renal dysfunction following cardiac transplantation is entirely due to the effects of CsA, as there are potential benefits of intervention. CsA undoubtedly has a deleterious effect on renal function, but it is not the only aetiological factor contributing toward renal damage following cardiac transplantation. Future studies should also address this, to allow further understanding of a common complication of cardiac transplantation.



   Notes
 
Correspondence and offprint requests to: Dr R. Dedi, Department of Renal Medicine, Leeds General Infirmary, Great George Street, Leeds, West Yorkshire, LS1 3EX, UK. Email: rdedi{at}doctors.org.uk Back



   References
 Top
 Introduction
 Cases
 Discussion
 References
 

  1. van Gelder T, Balk AH, Zietse R, Hesse C, Mochtar B, Weimar W. Renal insufficiency after heart transplantation: a case-control study. Nephrol Dial Transplant1998; 13: 2322–2326[Abstract]
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  8. Keck BM, Bennett LE, Fiol BS, Dally OP, Novick RJ, Hosenpud JD. Worldwide thoracic organ transplantation: a report from the UNOS/ISHLT International Registry for Thoracic Organ Transplantation. Clin Transplant1996; 31–45
  9. Erdoes LS, Hunter GC, Venerus BJ et al. Prospective evaluation of peripheral vascular disease in heart transplant recipients. J Vasc Surg1995; 22: 434–440[ISI][Medline]
  10. Postma CT, Bijlstra PJ, Rosenbusch G, Thien T. Pattern recognition of loss of early systolic peak by Doppler ultrasound has a low sensitivity for the detection of renal artery stenosis. J Hum Hypertens1996; 10: 181–184[ISI][Medline]
Received for publication: 9.12.01
Accepted in revised form: 7. 7.02





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