Miguel Gonzalez-Molina

Risk factors for graft loss and mortality after renal transplantation according to recipient age: a prospective multicentre study

Background To describe the causes of graft loss, patient death and survival figures in kidney transplant patients in Spain based on the recipients age. Methods The results at 5 years of post-transplant cardiovascular disease (CVD) patients, taken from a database on CVD, were prospectively analysed, i.e. a total of 2600 transplanted patients during 2000–2002 in 14 Spanish renal transplant units, most of them receiving their organ from cadaver donors. Patients were grouped according to the recipients age: Group A: <40 years, Group B: 40–60 years and Group C: >60 years. The most frequent immunosuppressive regimen included tacrolimus, mycophenolate mofetil and steroids. Results Patients were distributed as follows: 25.85% in Group A (>40 years), 50.9% in Group B (40–60 years) and 23.19% in Group C (>60). The 5-year survival for the different age groups was 97.4, 90.8 and 77.7%, respectively. Death-censored graft survival was 88, 84.2 and 79.1%, respectively, and non death-censored graft survival was 82.1, 80.3 and 64.7%, respectively. Across all age groups, CVD and infections were the most frequent cause of death. The main causes of graft loss were chronic allograft dysfunction in patients <40 years old and death with functioning graft in the two remaining groups. In the multivariate analysis for graft survival, only elevated creatinine levels and proteinuria >1 g at 6 months post-transplantation were statistically significant in the three age groups. The patient survival multivariate analysis did not achieve a statistically significant common factor in the three age groups. Conclusions Five-year results show an excellent recipient survival and graft survival, especially in the youngest age group. Death with functioning graft is the leading cause of graft loss in patients >40 years. Early improvement of renal function and proteinuria together with strict control of cardiovascular risk factors are mandatory.

Comparison of the long-term outcomes of kidney transplantation: USA versus Spain

BACKGROUND The long-term outcomes of kidney transplantation are suboptimal because many patients lose their allografts or experience premature death. Cross-country comparisons of long-term outcomes of kidney transplantation may provide insight into factors contributing to premature graft failure and death. We evaluated the rates of late graft failure and death among US and Spanish kidney recipients. METHODS This is a cohort study of US (n = 9609) and Spanish (n = 3808) patients who received a deceased donor kidney transplant in 1990, 1994, 1998 or 2002 and had a functioning allograft 1 year after transplantation with follow-up through September 2006. Ten-year overall and death-censored graft survival and 10-year overall recipient survival and death with graft function (DWGF) were estimated with multivariate Cox models. RESULTS Among recipients alive with graft function 1 year after transplant, the 10-year graft survival was 71.3% for Spanish and 53.4% for US recipients (P < 0.001). The 10-year, death-censored graft survival was 75.6 and 76.0% for Spanish and US recipients, respectively (P = 0.73). The 10-year recipient survival was 86.2% for Spanish and 67.4% for US recipients (P < 0.001). In recipients with diabetes as the cause of ESRD, the adjusted DWGF rates at 10 years were 23.9 and 53.8 per 1000 person-years for Spanish and US recipients, respectively (P < 0.001). Among recipients whose cause of ESRD was not diabetes mellitus, the adjusted 10-year DWGF rates were 11.0 and 25.4 per 1000 person-years for Spanish and US recipients, respectively. CONCLUSIONS US kidney transplant recipients had more than twice the long-term hazard of DWGF compared with Spanish kidney transplant recipients and similar levels of death-censored graft function. Pre-transplant medical care, comorbidities, such as cardiovascular disease, and their management in each countrys health system are possible explanations for the differences between the two countries.

Long-Term Improvement of Deceased Donor Renal Allograft Survival Since 1996: A Single Transplant Center Study

Background. The rate of acute rejection (AR) has decreased significantly, but whether this is associated with improvement in long-term graft survival is controversial. Methods. We analyzed 1445 consecutive adult deceased donor kidney transplant recipients from 1985 to 2005, over two periods (1985–1995 vs. 1996–2005) to compare long-term graft survival. Results. The second period was associated with older donors and recipients and a reduction in AR. A significant increase of 10.1 months at 11 years was seen in death-censored graft survival in 1996 to 2005. For this posttransplant time, graft half-life was 10.8 years in 1985 to 1995, while at this point in the second period 62% of recipients had a functioning graft. The yearly increase in serum creatinine was less pronounced in the latter period (0.05 mg/dL vs. 0.02 mg/dL, P<0.01). No difference was found in patient survival. Cox analysis showed that donor age (HR 1.02, P<0.001), AR (HR 1.72, P<0.001), panel-reactive antibody at transplantation (HR 1.01, P<0.001), and serum creatinine at 1 year (HR 2.01, P<0.001) had a negative impact on graft outcome. By contrast, the use of mycophenolate mofetil was associated with a 24% reduction in graft loss rate (HR 0.76, P<0.05). Conclusion. Long-term graft survival and renal function have improved in renal transplant recipients since 1996.

Effect of long-term steroid withdrawal in renal transplant recipients: a retrospective cohort study

Background. Steroids are largely effective for the immunosuppressive treatment in renal transplant patients, but cause severe side effects. Whether steroid withdrawal confers long-term beneficial effects remains unclear. Methods. Data on 4481 cadaveric kidney transplant recipients were collected to estimate the impact of steroid withdrawal on kidney function and graft and patient survival using multivariate Cox regression models. Results. A total of 923 patients (20.6%) had steroid treatment withdrawn. This was more common in recipients from younger donors and in older recipients, and in recipients with a first transplant, those who had pre-transplant or de novo diabetes mellitus and those with fewer episodes of acute rejection (AR) (22.4% vs. 29.2%, P < 0.001). Cox multivariate analysis stratifying by propensity scores showed that long-term steroid therapy was associated with a 70% increase in the risk of patient death. The repeated measures linear model showed that, although the abbreviated Modification of Diet in Renal Disease (aMDRD) values changed over time (P = 0.002), this was independent of steroid withdrawal (P = 0.08). In addition, of the 772 (17.2%) recipients who developed de novo diabetes mellitus, 204 (26.4%) ceased antidiabetic therapy, with more of these among those who ceased steroids (23% vs. 33.3%, P = 0.003). Blood pressure, cholesterol and triglyceride values were all significantly lower in the patients who ceased steroids. Conclusions. Steroid withdrawal in selected patients had no negative effect over time on renal function and graft survival, and it was associated with reduced mortality.

Health-related quality of life of patients receiving low-toxicity immunosuppressive regimens: a substudy of the Symphony Study.

Objective. To evaluate health-related quality of life (HRQoL) in patients with different low-toxicity regimens posttransplantation. Methods. One hundred fifty-six patients were randomized to standard-dose cyclosporine A (CsA), mycophenolate mofetil, and corticosteroids or daclizumab induction, mycophenolate mofetil, and corticosteroids with a low dose of CsA, tacrolimus (Low-Tac), or sirolimus. SF-36 Health survey was completed at baseline, 3, 6, and 12 months. Results. There were no differences between groups in SF-36 at baseline or at month 12. Low-Tac showed higher scores at month 3 than standard-dose CsA and low dose of CsA. Patients with serum creatinine less than or equal to 1.5 mg/mL had better HRQoL at 6 and 12 months. Proportion of these patients was higher in Low-Tac at 6 months. Physical component summary of Patients increased during follow-up, but mental component summary did not. Patients with acute rejection showed lower mental component summary at 6 months. Conclusions. No HRQoL differences were identified among groups, but the low-dose Tac group showed the fastest improvement.

Cost of prophylaxis in the management of cytomegalovirus infection in solid organ transplant recipients

Abstract:  Background:  Limited economic data exist on the use of valganciclovir for the prevention of cytomegalovirus (CMV) infection and disease in solid organ transplant (SOT) recipients. We compared the economics of sequential i.v. and oral ganciclovir prophylaxis vs. oral valganciclovir prophylaxis alone in high‐risk (D+/R−) SOT patients.

Immune response and histology of humoral rejection in kidney transplantation

The adaptive immune response forms the basis of allograft rejection. Its weapons are direct cellular cytotoxicity, identified from the beginning of organ transplantation, and/or antibodies, limited to hyperacute rejection by preformed antibodies and not as an allogenic response. This resulted in allogenic response being thought for decades to have just a cellular origin. But the experimental studies by Gorer demonstrating tissue damage in allografts due to antibodies secreted by B lymphocytes activated against polymorphic molecules were disregarded. The special coexistence of binding and unbinding between antibodies and antigens of the endothelial cell membranes has been the cause of the delay in demonstrating the humoral allogenic response. The endothelium, the target tissue of antibodies, has a high turnover, and antigen-antibody binding is non-covalent. If endothelial cells are attacked by the humoral response, immunoglobulins are rapidly removed from their surface by shedding and/or internalization, as well as degrading the components of the complement system by the action of MCP, DAF and CD59. Thus, the presence of complement proteins in the membrane of endothelial cells is transient. In fact, the acute form of antibody-mediated rejection was not demonstrated until C4d complement fragment deposition was identified, which is the only component that binds covalently to endothelial cells. This review examines the relationship between humoral immune response and the types of acute and chronic histological lesion shown on biopsy of the transplanted organ.

Survival in Southern European patients waitlisted for kidney transplant after graft failure: A competing risk analysis

Background Whether patients waitlisted for a second transplant after failure of a previous kidney graft have higher mortality than transplant-näive waitlisted patients is uncertain. Methods We assessed the relationship between a failed transplant and mortality in 3851 adult KT candidates, listed between 1984–2012, using a competing risk analysis in the total population and in a propensity score-matched cohort. Mortality was also modeled by inverse probability weighting (IPTW) competing risk regression. Results At waitlist entry 225 (5.8%) patients had experienced transplant failure. All-cause mortality was higher in the post-graft failure group (16% vs. 11%; P = 0.033). Most deaths occurred within three years after listing. Cardiovascular disease was the leading cause of death (25.3%), followed by infections (19.3%). Multivariate competing risk regression showed that prior transplant failure was associated with a 1.5-fold increased risk of mortality (95% confidence interval [CI], 1.01–2.2). After propensity score matching (1:5), the competing risk regression model revealed a subhazard ratio (SHR) of 1.6 (95% CI, 1.01–2.5). A similar mortality risk was observed after the IPTW analysis (SHR, 1.7; 95% CI, 1.1–2.6). Conclusions Previous transplant failure is associated with increased mortality among KT candidates after relisting. This information is important in daily clinical practice when assessing relisted patients for a retransplant.

Mortality in Elderly Waiting-List Patients Versus Age-Matched Kidney Transplant Recipients: Where is the Risk?

The number of elderly patients on the waiting list (WL) for kidney transplantation (KT) has risen significantly in recent years. Because KT offers a better survival than dialysis therapy, even in the elderly, candidates for KT should be selected carefully, particularly in older waitlisted patients. Identification of risk factors for death in WL patients and prediction of both perioperative risk and long-term post-transplant mortality are crucial for the proper allocation of organs and the clinical management of these patients in order to decrease mortality, both while on the WL and after KT. In this review, we examine the clinical results in studies concerning: a) risk factors for mortality in WL patients and KT recipients; 2) the benefits and risks of performing KT in the elderly, comparing survival between patients on the WL and KT recipients; and 3) clinical tools that should be used to assess the perioperative risk of mortality and predict long-term post-transplant survival. The acknowledgment of these concerns could contribute to better management of high-risk patients and prophylactic interventions to prolong survival in this particular population, provided a higher mortality is assumed.

Peripheral Vascular Disease and Death in Southern European Kidney Transplant Candidates: A Competing Risk Modeling Approach

Background The association between peripheral vascular disease (PVD) and survival among kidney transplant (KT) candidates is uncertain. Methods We assessed 3851 adult KT candidates from the Andalusian Registry between 1984 and 2012. Whereas 1975 patients received a KT and were censored, 1876 were on the waiting list at any time. Overall median waitlist time was 21.2 months (interquartile range, 11-37.4). We assessed the association between PVD and mortality in waitlisted patients using a multivariate Cox regression model, with a competing risk approach as a sensitivity analysis. Results Peripheral vascular disease existed in 308 KT candidates at waitlist entry. The prevalence of PVD among nondiabetic and diabetic patients was 4.5% and 25.3% (P < 0.0001). All-cause mortality was higher in candidates with PVD (45% vs 21%; P < 0.0001). Among patients on the waiting list (n = 1876) who died (n = 446; 24%), 272 (61%) died within 2 years after listing. Cumulative incidence of all-cause mortality at 2 years in patients with and without PVD was 23% and 6.4%, respectively (P < 0.0001); similar differences were observed in patients with and without diabetes. By competing risk models, PVD was associated with a 1.9-fold increased risk of mortality (95% confidence interval [95% CI], 1.4-2.5). This association was stronger in waitlisted patients without cardiac disease (subhazard ratio, 2.2; 95% CI, 1.6-3.1) versus those with cardiac disorders (subhazard ratio, 1.5; 95% CI, 0.9-2.5). No other significant interactions were observed. Similar results were seen after excluding diabetics. Conclusions Peripheral vascular disease is a strong predictor of mortality in KT candidates. Identification of PVD at list entry may contribute to optimize targeted therapeutic interventions and help prioritize high-risk KT candidates.