Causes of death after renal transplantation

J. Douglas Briggs

Chairman, ERA–EDTA Registry, Academic Medical Centre, Amsterdam, The Netherlands

Keywords: renal transplantation; mortality; cardiovascular disease; malignancy; infection

Introduction

The survival of patients who undergo renal transplantation has improved considerably over the past three decades. At present one can expect a survival rate of 95% at 1 year and around 90% at 3–5 years. The risk of death has fallen over the years in all categories of patients but this is evident especially in the older age groups and in those with considerable comorbid disease such as many of the patients with diabetes mellitus. For example, in the mid 1970s 1-year patient survival in those over 35 years of age was only around 60% while in the younger adult it was around 85%. By the 1990s the difference had narrowed to just over 5% with 1-year survival at or just below 90% for older patients and at or just above 95% for younger adult recipients. Thus in the short term, renal transplantation now offers a good prospect of survival for patients who are free of major comorbid illness. However, life expectancy beyond 10 years is still considerably less than in the general population and this is mainly for two reasons. The first is comorbid illness affecting the cardiovascular system, some degree of which is an almost inevitable accompaniment of a period of chronic renal failure. The other factor which has an important adverse impact on long-term survival is malignant disease. These two groups of diseases are the main contributors to death following transplantation and most of this review will be devoted to them. A third group is infective illness and while this remains important, it leads to death much less often than in the past. The reduction in death from infection is the main reason for the considerable improvement over the years in the 1-year survival rate.

Although long-term survival following renal transplantation remains considerably below that of the general population, it is much superior to that experienced by dialysis patients. In a US Renal Data System analysis of just under 50 000 dialysis patients who were placed on the transplant waiting list, the long-term mortality risk was 68% lower among those receiving transplants when compared with patients remaining on the waiting list [1].

Causes of death

In order to obtain a true picture of the relative frequency of the causes of death following renal transplantation, one has to take into account five factors each of which have a major influence. These are; patient age, the time interval since the transplant, whether the recipient has diabetes mellitus, the geographical position of the transplant centre and the era in which the transplant was performed. The last is not only of historical interest, but is important for a number of reasons. For example, we need to know if changing immunosuppressive regimens are influencing the mortality from cancer. Table 1Go shows a breakdown of the three main causes of death from four sources, the USRDS and ERA-EDTA data bases and two single centre European studies [25]. The higher percentage of cardiovascular deaths in the Glasgow patients than elsewhere to some extent will reflect the high background level of cardiovascular death in Scotland. The higher figure will however also be influenced by the small number of deaths in the ‘other/unknown’ group in comparison with the other three series.


View this table:
[in this window]
[in a new window]
 
Table 1. Causes of death following renal transplantation

 
The effect of the era within which the transplant was carried out can be seen by examination of the Glasgow figures. During the first 14 years of the transplant programme (1969–1982), 40% of deaths were due to infection, 23% to cardiovascular disease and 10% to malignancy. During the subsequent 14 years, deaths occurring from infection fell substantially with considerably more deaths from cardiovascular disease and malignancy both relatively and in absolute terms. The increased cardiovascular mortality probably reflects an older population of patients in more recent years.

Cardiovascular disease

Table 1Go shows that cardiovascular disease is the leading cause of death following renal transplantation accounting for 40–55% of all deaths. While it is much commoner in transplant patients, its contribution to post-transplant mortality to some extent reflects the incidence of cardiac disease in the general population and as a consequence the incidence varies widely between countries. An ERA–EDTA Registry analysis showed that the death rate from ischaemic heart disease in patients on renal replacement therapy was around five times higher in most countries than in the general population [6]. There are four broad subdivisions of cardiovascular disease namely coronary artery disease, left ventricular hypertrophy (LVH), cerebrovascular and peripheral vascular disease. It is not helpful to try to determine the precise contribution of each to overall mortality but it is more useful to examine the mechanisms of disease with a view to implementing preventive and therapeutic measures. The three main mechanisms of cardiovascular disease and their contributing factors are shown in Table 2Go. Most of the causative factors leading to atheroma can be influenced but to be fully effective the necessary measures need to be started early in the natural history of this process and that means not only before the transplant but indeed in most cases well before the start of dialysis. Smoking is the most important adverse factor. An analysis of 434 transplant patients in our centre showed smokers to have a more than two times increased risk of cardiovascular death when compared with non-smokers with a hazard ratio of 2.2 and P value of <0.001 [7]. Kasiske and Klinger have published very similar figures [8]. There are numerous reports documenting hyperlipidaemia following renal transplantation and a correlation between both hypertriglyceridaemia and low HDL and ischaemic heart disease has been confirmed [9]. While statins have been found to improve the lipid profile in transplant recipients without undue side-effects [10], proof that they will ameliorate the cardiovascular disease in these patients is still awaited. While hyperhomocysteinaemia has also been shown to be an independent cardiovascular risk factor in renal transplant recipients [11], evidence for benefit from folic acid is also still awaited. The control of hyperglycaemia, regular exercise and steps to induce weight loss in obese patients are all logical but as yet not of proven value in this population.


View this table:
[in this window]
[in a new window]
 
Table 2. Mechanisms of cardiovascular disease following renal transplantation

 
Although all the therapeutic measures which have been discussed have the potential to reduce atheroma, the incidence is so high particularly in the most predisposed groups such as the older and the diabetic patient that overt cardiovascular disease will remain a common complication. Also one has to remember that the immunosuppressive therapy which is necessary to avoid premature graft loss may increase the tendency to atheroma. Mycophenolate mofetil and azathioprine are free of this effect but rapamycin causes hyperlipidaemia and steroids, cyclosporin and tacrolimus have multiple adverse effects on the cardiovascular system.

Left ventricular hypertrophy begins early in the course of chronic renal failure, being present in 45% of patients by the time the creatinine clearance has fallen below 25 ml/min [11] and in 70% by the time of starting dialysis [13]. With increasing time on dialysis the degree of LVH tends to increase [14]. By contrast there is a tendency to regression of the LVH following transplantation as some of the mechanisms such as anaemia and fluid overload cease to be operative [15]. Despite this tendency to regression of LVH, its presence at the time of transplantation is an adverse prognostic factor for subsequent patient survival [16]. Following transplantation the most important causative factor for persisting LVH is almost certainly hypertension. Blood pressure control is often suboptimal and in a survey in my own centre 32% of transplant recipients had unsatisfactory blood pressure control [17]. This study was not able to show an association between blood pressure and patient survival, although there was an association between both systolic blood pressure and pulse pressure and graft survival. This association supports the view that good blood pressure control following transplantation is beneficial to graft survival while there is in addition the likelihood of reducing the degree of LVH. A target blood pressure of less than 130/80 is probably appropriate. Although it is unlikely to be the most important factor, the presence of the DD genotype of the ACE gene has been shown to be associated with LVH following transplantation [18]. The same research group has also found that the DD genotype predicts a more favourable blood pressure response to ACE inhibitors than the other genotypes [19].

The third predisposing factor to cardiovascular disease which is outlined in Table 2Go is vascular calcification. This occurs even before the age of 30 years in dialysis patients [20] and will have a deleterious effect on the vascular tree. However, its role in producing end-organ damage relative to that of atheroma has still to be fully worked out.

Malignancy

Skin cancer especially of the squamous cell type is extremely common following organ transplantation and by 20 years post-transplant will have occurred in 50% of patients in high incidence areas such as Australia [20]. However, a fatal outcome in this group of patients is uncommon. Solid organ cancer is less common with a 20% probability of its development by 20 years post-transplant [21]. The prognosis in these patients is very poor with a median survival from the time of diagnosis of just under 4 months in my own centre. It is somewhat ironic that the graft survival in these patients with solid organ cancer—if censored for patient death—is significantly better than average suggesting that they have a degree of immunological hyporesponsiveness. In comparison with the general population there are a few types of malignancy that occur much more commonly. The sites of these include lip, anogenital region (rectal and vulval), hepatobiliary, renal and thyroid. However, most of the tumours encountered in the transplant recipient are the ones that are common also in the general population such as lung, stomach, colon and prostate. Treatment is very unsatisfactory in these transplant patients due at least in part to the frequent presence of widespread tumour at the time of presentation. My own practice is usually to withdraw immunosuppression apart from low dose steroids but there is no evidence that such withdrawal is of value.

Virus-related tumours are of particular importance in view of the potential for prevention or cure using anti-viral therapy. The types currently recognized are shown in Table 3Go. Post- transplant lymphoproliferative disorder (PTLD) often presents within months or 2–3 years of the transplant. Predisposing factors are primary Epstein Barr virus (EBV) infection in a seronegative recipient and powerful immunosuppression such as OKT3. There is potential scope for prophylaxis by avoidance of transplanting kidneys from EBV positive donors into seronegative recipients and by the use of antiviral therapy such as ganciclovir [22]. It is now clearly established that Kaposi's sarcoma is linked with human herpes virus 8 (HHV8) infection. It is also much commoner in patients of African and Middle Eastern origin and in those receiving heavy immunosuppression [23]. Remission can be induced by withdrawing immunosuppression and giving alpha interferon and/or radiotherapy in 50% of patients with visceral involvement and 75% of those without such involvement. Finally there is still no effective anti-viral therapy available for patients with the various human papilloma virus-associated tumours. With increasing numbers of renal transplant recipients now experiencing graft survival of more than 10 or 20 years the number developing malignancies is unfortunately going to continue to increase.


View this table:
[in this window]
[in a new window]
 
Table 3. Virus related tumours

 

Infection

As one can see from Table 1Go infection in the recent past has accounted for around 15–20% of deaths following renal transplantation. The reduction both in deaths from infection, and in the incidence and severity of acute rejection are undoubtedly the two most encouraging improvements in transplant outcome which have taken place over the past 25 years. Although the incidence of fatal infection has fallen over the years sufficiently detailed registry data to permit examination of the change in pattern of infective deaths is not available.

A detailed discussion of even the more common types of infection would not be appropriate in this brief review. There are numerous comprehensive reviews available of post-transplant infection such as the recent one by Fishman and Rubin [24]. That review reminds us that in the first month post-transplant, bacterial infections predominate while during the subsequent 6 months one may also encounter opportunistic infections of which cytomegalovirus is the commonest. Beyond the first six months, again bacterial infections predominate. Table 4Go gives a breakdown of the different types of fatal infection from a recent ERA–EDTA Registry report. This shows that deaths from bacterial infections predominate with those resulting from opportunistic infections accounting for only a small percentage. Septicaemia accounted for almost half of deaths. While information on the sites of infection associated with the septicaemia is not available, the main sites in transplant as in other surgical patients are the urinary, biliary and intestinal tracts, the lungs and surgical wounds.


View this table:
[in this window]
[in a new window]
 
Table 4. Deaths from infection following renal transplantationa

 
There are four important aspects to the avoidance of infective deaths. These are patient selection, prophylactic measures, early diagnosis and effective treatment. As a general rule, patients with active infection such as tuberculosis, bronchiectasis or skin ulcers in the diabetic patient should not be on the transplant waiting list. Examples of useful prophylactic measures are ganciclovir and cotrimoxazole to prevent cytomegalovirus and pneumocystis carinii infection respectively in high risk patients. Specific diagnostic tests and effective treatment are now available for all the commonly encountered infections. Two important principles of management are to have a high index of suspicion in view of the frequent absence of clear cut signs of infection and to reduce or discontinue immunosuppression earlier rather than later in the presence of serious infection.

Miscellaneous causes of death

Gastro-intestinal complications such as perforation of peptic ulcer or colon, acute pancreatitis, pulmonary embolus, liver disease and haemorrhage from various sites each account for 1–2% of deaths while most of the remaining miscellaneous group are accounted for by ‘cause unknown’.

Conclusions

There has been an encouraging decrease in mortality following renal transplantation during the past 25 years particularly during the early post-transplant period. This has resulted mainly from safer surgery and anaesthesia and fewer infective deaths. Cardiovascular and malignant diseases now between them account for most deaths. A slow but steady reduction in cardiovascular deaths is nowadays a feasible medium term aim, while progress in the prevention of malignancy is a more distant target.

Notes

Correspondence and offprint requests to: J. D. Briggs, 48 Kingsborough Gardens, Glasgow G12 9NL, UK. Back

References

  1. Wolfe RA, Ashby VB, Milford EL, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation and recipients of a first cadaver transplant. New Engl J Med 1999; 341: 1725–1730[Abstract/Free Full Text]
  2. Ojo AO, Hanson JA, Wolfe RA, Leichtman AB, Agodoa LY, Port FK. Long-term survival in renal transplant recipients with graft function. Kidney Int 2000; 57: 307–313[ISI][Medline]
  3. Jager K. Unpublished observations
  4. Briggs JD. Unpublished observations
  5. Arend SM, Mallat MJK, Westendorp RJW, van der Woude FJ, van Es LA. Patient survival after renal transplantation, more than 25 years follow-up. Nephrol Dial Transplant 1997; 12: 1672–1679[Abstract]
  6. Raine AEG, Margreiter R, Brunner FP, et al. Report on management of renal failure in Europe, XXII 1991. Nephrol Dial Transplant 1992; 7 [suppl 2]: 7–35[ISI][Medline]
  7. McLean D, Hay P, Woo YM, Padmanabhan N, Jardine AG. Cardiovascular risk and renal transplantation: a mathematical model to explore future strategies. In: Timio M, Wizemann V, Venanzi S, Eds. Cardionephrology 6. Cosenza Editoriale Bios, 2000; 233–237
  8. Kasiske BL, Klinger D. Cigarette smoking in renal transplant recipients. J Am Soc Nephrol 2000; 11: 753–759[Abstract/Free Full Text]
  9. Kasiske BL, Guijarro C, Massy ZA, Wiederkehr MR, Ma JZ. Cardiovascular disease after renal transplantation. J Am Soc Nephrol 1996; 7: 158–165[Abstract]
  10. Li PKT, Mak TWL, Chan TH, Wang A, Lam CWK, Lai KN. Effect of fluvastatin on lipoprotein profiles in treating renal transplant recipients with dyslipoproteinemia. Transplantation 1995; 60: 652–656[ISI][Medline]
  11. Ducloux D, Motte G, Challier B, Gibey R, Chalopin J-M. Serum total homocysteine and cardiovascular disease occurrence in chronic, stable renal transplant recipients: a prospective study. J Am Soc Nephrol 2000; 11: 134–137[Abstract/Free Full Text]
  12. Levin A, Singer J, Thompson CR, Ross H, Lewis M. Prevalent left ventricular hypertrophy in the predialysis population: identifying opportunities for intervention. Am J Kidney Dis 1996; 27: 347–354[ISI][Medline]
  13. Harnett JS, Kent GM, Foley RN, Parfrey PS. Cardiac function and haematocrit level. Am J Kidney Dis 1995; 25 [Suppl 1]: S3–S7[Medline]
  14. Foley RN, Parfrey PS, Kent GM, Harnett JD, Murray DC, Barre PE. Long-term evolution of cardiomyopathy in dialysis patients. Kidney Int 1998; 54: 1720–1725[ISI][Medline]
  15. Parfrey PS, Harnett JD, Foley R N, et al. Impact of renal transplantation on uremic cardiomyopathy. Transplantation 1995; 60: 908–914[ISI][Medline]
  16. McGregor E, Stewart G, Rodger RSC, Jardine AG. Early echocardiographic changes and survival following renal transplantation. Nephrol Dial Transplant 2000; 15: 93–98[Abstract/Free Full Text]
  17. Stewart GA, Tan CC, Rodger RSC, et al. Graft and patient survival following renal transplantation: new targets for blood pressure control. In: Timio M, Wizeman V, Venanzi S, Eds. Cardionephrology 5. Cosenza: Editoriale Bios, 1999; 357–361
  18. Hernandez D, Lacalzada J, Rufino M, et al. Prediction of left ventricular mass changes after renal transplantation by polymorphism of the angiotensin-converting-enzyme gene. Kidney Int 1997; 51: 1205–1211[ISI][Medline]
  19. Hernandez D, Lacalzada J, Salido E, et al. Regression of left ventricular hypertrophy by lisinopril after renal transplantation: Role of ACE gene polymorphism. Kidney Int 2000; 58: 889–897[ISI][Medline]
  20. Goodman WG, Goldin J, Kuizon BD, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. New Engl J Med 2000; 342: 1478–1483[Abstract/Free Full Text]
  21. Sheil AGR. Cancer in dialysis and transplant patients. In: Morris PJ, Ed. Kidney Transplantation. Prinicples and practice. Philadelphia, W B Saunders Company, 1994; 390–400
  22. Boubenider S, Hiesse C, Goupy C, Kriaa F, Marchand S, Charpentier B. Incidence and consequences of post-transplantation lymphproliferative disorders. J Nephrol 1997; 10: 136–145[ISI][Medline]
  23. Farge D, Lebbé C, Marjanovic Z, et al. Human herpes virus-8 and other risk factors for Kaposi's sarcoma in kidney transplant recipients. Transplantation 1999; 67: 1236–1242[ISI][Medline]
  24. Fishman JA, Rubin RH. Infection in organ-transplant recipients. New Engl J Med 1998; 338: 1741–1751[Free Full Text]