Mitchell L. Henry

Report of the Crystal City Meeting to Maximize the Use of Organs Recovered from the Cadaver Donor

A consensus meeting to develop guidelines that would improve the recovery and transplantation of organs from the cadaver donor was held on 28–29 March 2001, in Crystal City, Virginia, sponsored by the American Society of Transplant Surgeons and the American Society of Transplantation. The crisis in organ supply persists and the continuing shortage presents a compelling responsibility for the transplant community to maximize the use of organs procured from cadaver donors.

The impact of mycophenolate mofetil dosing patterns on clinical outcome after renal transplantation

Abstract: Background:  Mycophenolate mofetil (MMF) has proven to be a very effective drug for the prevention of acute rejection following renal transplantation when dosed as prescribed at 2 or 3 g/d. However, circumstances arise in clinical transplantation where the dose must be lowered, either to avoid drug toxicity or because of concurrent infection. The impact on the incidence of acute rejection and graft survival when the MMF dose must be lowered has not previously been investigated.

Impact of acute rejection and early allograft function on renal allograft survival

Both acute rejection and the function of a renal allograft early after transplantation correlate with long-term graft survival. In this study we assessed the relationship between these two factors in 843 adult recipients of first cadaveric renal grafts, transplanted at a single institution and followed for a minimum of 3.5 years. Patients were divided into four groups according to (1) history of acute rejection (AR) during the first 6 months after transplantation, and (2) concentration of serum creatinine at 6 months after transplantation (SCr(6mo) < or > or = 2 mg/dl). Death censored allograft survival was not significantly different among patients without AR and with low SCr(6mo) (group 1, n=376), patients without AR but with an elevated SCr(6mo) (group 2, n=117), and patients with AR but low SCr(6mo) (group 3, n=185). In contrast, graft survival was significantly worse in patients with AR and an elevated SCr(6mo) (group 4, n=165) compared with patients in the other three groups (Cox, P<0.0001). The elevated SCr(6mo) in group 4 patients was not necessarily the consequence of AR, as 32% of patients in group 4 had a SCr at 10 days after transplantation (SCr(10d)), before they had AR, that was equal to or higher than the SCr(6mo). Based on this observation we investigated the implications of the SCr(10d) concentration for graft prognosis. The SCr(10d) correlated weakly with graft survival (Cox, P=0.05). However, an elevated SCr(10d) correlated with other potential risk factors for graft survival including: Older donors (P<0.0001), male recipients (P<0.0001), and heavier recipients (P<0.0001, all by multivariate regression); and posttransplant factors such as, increasing numbers of AR (P<0.0001), higher posttransplant blood pressure (P<0.0001), and lower doses of cyclosporine (P<0.0001, all by multivariate regression). In conclusion, graft dysfunction predicts poor graft survival only when associated with AR. Similarly, AR predicts a poor renal allograft survival only when associated with graft dysfunction. The SCr(10d) is an indicator of risk factors from both the donor and recipient, and an elevated SCr(10d) predicts a higher risk of acquiring additional risk factors early after transplantation.

Medication compliance following renal transplantation.

BACKGROUND There appears to be general consensus that a relationship exists between noncompliance and clinical outcomes in health care, including renal transplantation. This study investigated variables associated with medication noncompliance after renal transplantation. METHODS A mail survey containing objective and subjective variables was sent to individuals who met eligibility criteria. Medication compliance was measured by two items: 1) Frequency of forgetting to take medications and 2) Frequency of not taking medications exactly as prescribed. Descriptive and multivariate analyses were utilized to examine the data. RESULTS Individuals who were older and those who perceived less pain were less likely to forget medications. The belief that health outcomes were controlled by chance and feeling bothered by part of the transplant experience were associated with greater likelihood of forgetting medications. Individuals who perceived a higher level of social functioning and those who believed that health outcomes were controlled by powerful others were more likely to take medications exactly as prescribed. An internal locus of control for health outcomes and feeling bothered by part of the transplant experience were associated with less likelihood of taking medication exactly as prescribed. CONCLUSIONS The finding of this study suggest that compliance with medications after renal transplant is associated with subjective, not objective variables. Positive feelings regarding their physicians and the transplant experience increased compliance. Combining consistent measurement of compliance, examination of its relationship to clinical outcomes, and appreciation for the patient perspective should result in increased levels of compliance and better clinical outcomes.

Renal transplantation in older people

Renal transplantation in people 60 years old or more is controversial due to the morbidity associated with immunosuppression and the scarcity of renal allografts. We have reviewed the outcome of 1222 consecutive renal transplants done at a single institution with a uniform immunosuppressive protocol over 10 years. 5-year graft survival was the same in the under sixties as in the sixties and over. Patient survival was worse in the older group (p = 0.0001), but there were significantly fewer immunological graft losses: 11% vs 31% (p = 0.0009; relative risk [RR] = 0.36 [95% confidence interval 0.19-0.66]). A majority of the deaths in both groups were secondary to cardiovascular disease, not due to complications of immunosuppression. We conclude that renal transplantation in people 60 and over has results equivalent to a younger population. Age 60 and over should not be a major factor in considering if a patient is eligible for renal transplantation.

Cyclosporine and tacrolimus (FK506): A comparison of efficacy and safety profiles

Multicenter clinical trials conducted in the United States and Europe to compare the efficacy and safety of cyclosporine with tacrolimus (FK506) have demonstrated comparable long‐term patient survival and graft survival in liver and renal transplant recipients. Importantly, treatment with tacrolimus was associated with reductions in the incidence and severity of acute rejection episodes. However, tacrolimus‐based therapy was also associated with increased toxicities in comparison to conventional cyclosporine‐based therapy. It is becoming increasingly accepted that earlier trials may have employed high or supratherapeutic doses of tacrolimus and may have been unbalanced with respect to study design. In addition, these pivotal comparative trials were performed with the original formulation of cyclosporine, and not the cyclosporine microemulsion preparation. This critical review of the literature focuses on the United States and European tacrolimus multicenter clinical trials and examines the efficacy and safety of the two primary immunosuppressants, cyclosporine and tacrolimus, obtained in these and other studies. The preliminary findings of ongoing studies comparing the efficacy and safety of the improved formulation, cyclosporine microemulsion, with tacrolimus are also discussed. The overall efficacy of the two agents appears to be similar. The safety profile shows differing toxicities of the two medications. The availability of these two immunosuppressants allows the clinician improved options when choosing an immunosuppressive regimen in solid organ transplantation.

Improving the prediction of donor kidney quality: deceased donor score and resistive indices.

Background. The deceased donor score (DDS), expanded criteria donor (ECD) definition, and resistive index (RI) were developed for pretransplant evaluation of donors. DDS and ECD are determined by a calculation of risk from donor variables, while RI is determined from flow characteristics of kidneys during machine preservation (MP). This study was designed to compare DDS, ECD status, and RI as predictors of outcome after deceased donor transplantation. We were also interested to see if DDS or ECD could identify kidneys most likely to benefit from MP. Methods. We retrospectively reviewed 48,952 deceased donor renal transplants reported to UNOS from 1997–2002. DDS (0-39 pts.), ECD status (+ or −), and preservation technique (MP vs. cold storage [CS]) were determined in all cases. RI during MP was studied in a single-center cohort of 425 transplants. Results. DDS was superior to ECD status and RI in its correlation with early and late renal function after transplantation. DDS identified a subgroup of ECD- kidneys, those with DDS ≥20 pts, that functioned significantly below expectation and similar to ECD+ kidneys. Benefits of MP, which include improved early graft function and a trend towards longer graft survival, were greatest in the group of kidneys with DDS ≥20 pts. Conclusions. DDS was the best predictor of outcome after deceased donor renal transplantation and may be useful in identifying kidneys most likely to benefit from MP.

Patient survival after renal transplantation: II. The impact of smoking

Renal transplant recipients have significantly higher mortality than individuals without kidney disease and the excess mortality is mainly due to cardiovascular causes. In this study, we sought to determine the impact of smoking, a major cardiovascular risk factor, on patient and renal graft survival. The study population included all adult recipients of first cadaveric kidney transplants done in our institution from 1984 to 1991. By selection, all patients were alive and had a functioning graft for at least 1 yr after transplantation. Smoking history was gathered prior to transplantation. The follow‐up period was 84.3±41 months and during this time 28% of the patients died and 21% lost their graft. By univariate and multivariate analysis, patient survival, censored at the time of graft loss, correlated with these pre‐transplant variables: age (p<0.0001); diabetes (p=0.0002); history of cigarette smoking (p=0.004); time on dialysis prior to the transplant (p=0.0005); and cardiomegaly by chest X‐ray (p=0.0005). Post‐transplant variables did not correlate with patient mortality. By Cox regression, patient survival time was significantly shorter in diabetics (p<0.0001), smokers (p=0.0005), and recipients older than 40 yr. However, there were no significant differences between the survival of smokers, non‐diabetics, diabetics, and older recipients. Patient death was the most common cause of renal transplant failure in smokers, in patients older than 40 yr, and in diabetics, but these patient characteristics did not correlate with graft survival. The prevalence of different causes of death was not significantly different between smokers and non‐smokers. In conclusion, a history of cigarette smoking correlates with decreased patient survival after transplantation, and the magnitude of the negative impact of smoking in renal transplant recipients is quantitatively similar to that of diabetes.

Factors related to the donor organ are major determinants of renal allograft function and survival

In this study, we analyzed the relative impact of donor and recipient variables on cadaveric renal allograft function and survival. The unique feature of the study population is that each pair of recipients received their allografts from a single donor. The study includes 378 adult patients. In 129 pairs both recipients were Caucasian, and in 60 pairs one recipient was Caucasian and the other was African-American. All transplants were done in one center, thus minimizing differences in preservation time and providing uniform posttransplant management. The initial analysis showed a relationship between the function of the allograft 6 months after transplantation (serum creatinine [SCr]6 mo) and donor variables (P = 0.0004, analysis of variance). Furthermore, it was calculated that 64% of the variability in the SCr 6mo among patients was due to donor factors and 36% was due to recipient factors. An elevated SCr 6 mo was significantly associated with older donors, male recipients, and patients with acute rejection episodes. Furthermore, other unidentified donor factors may have an impact on allograft function. Reflecting the importance of donor factors, there was a significant relationship between SCr 6mo in paired recipients (P < 0.0008 by Spearman). Analysis of racially dissimilar pairs showed that the SCr 6mo and graft survival 6 months after transplantation were not significantly different between Caucasians and African-Americans. However, beyond 6 months, graft survival was worse in African-Americans (P < 0.0001 by Cox). Compared with Caucasians, graft survival was significantly worse in African-Americans with poorly controlled blood pressure (mean arterial pressure > 105 mmHg) (P = 0.002, Cox), but not in those patients with mean arterial pressure < 105 mmHg. In conclusion, donor factors are major determinants of renal allograft function. However, those factors may not be easily identifiable or quantifiable. Donor factors do not contribute to racial differences in allograft survival. However, poorly controlled hypertension correlates with poor renal graft survival in African-Americans.

The high prevalence of severe early posttransplant renal allograft pathology in hepatitis C positive recipients.

In the USA approximately 10% of candidates for renal transplantation have serum antibodies to hepatitis C (HCV). To assess the possible impact of HCV infection on early posttransplant events we assessed allograft complications during the first 6 months following renal transplantation in three groups of adult renal allograft recipients: (1) HCV antibody positive recipients (R-HCV) (n=32); (2) HCV negative recipients who received kidneys from HCV antibody positive donors (D-HCV) (n=48); and (3) HCV negative recipients of HCV negative allografts who were transplanted during the same time period as R-HCV (Ctrl) (n=204). Allograft biopsies were done for evaluation of allograft dysfunction during the first 6 months posttransplant in 58% of Ctrl, 42% of D-HCV, and 63% of R-HCV (not significantly different). The prevalence of acute tubulointerstitial rejection was similar among the 3 groups of patients. In contrast, compared with Ctrl, both R-HCV and D-HCV had a significantly higher prevalence of acute transplant glomerulopathy (Ctrl, 6%; R-HCV, 55%, P<.0001; D-HCV 40%, P=.0004). Acute vascular rejection was more common in R-HCV (60%) than in Ctrl (28%) (P=.009) and the prevalence of chronic vascular rejection was also higher in R-HCV (60%) than in Ctrl (31%) (P=.01). Furthermore, chronic vascular rejection was diagnosed earlier in R-HCV (64% of cases within one month posttransplantation) than in Ctrl (19% within one month) (P=.01). Death censored renal allograft losses occurred in 14% of Ctrl, 17% of D-HCV, and 26% of R-HCV (not significant). In conclusion, R-HCV patients have a high prevalence of severe acute pathologic findings in renal allograft biopsies obtained early after transplantation and develop chronic vascular rejection more often and earlier than HCV negative recipients. These studies also confirm the previously reported association of HCV with acute transplant glomerulopathy.