Predictors of Early and Late Mortality in Older Kidney Transplant Recipients.

BACKGROUND: Older kidney patients with chronic kidney disease benefit significantly from kidney transplantation. However, these older transplant recipients have greater mortality after transplantation than younger transplant recipients. Understanding the impact of comorbidities on post-transplant mortality can improve risk stratification and patient selection. METHODS: A single-center analysis of 3105 kidney transplant recipients was performed over a 12-year period. Comorbidities associated with death were evaluated in older and younger transplant recipients. RESULTS: The 2 most important factors associated with increased mortality in the first 100 days after transplant were recipient age ≥60 and receipt of deceased donor organs (adjusted odds ratios, 3.29 and 5.80, respectively), with no statistically significant impact of recipient comorbidities. In the later post-transplant period (after the first 100 days), recipient age ≥60 and receipt of deceased donor organs (adjusted hazard ratios [HR] of 2.14 and 2.29, respectively) remained predictors of mortality. We also found that donor age ≥60 and the recipient having cardiovascular disease and diabetes were independent predictors of increased mortality. There was a statistically significant interaction between diabetes and heart disease and recipient age ≥60, with a lesser impact on late mortality in older patients compared to younger patients. CONCLUSIONS: This analysis suggests that comorbidities have a larger impact later after transplantation, with less effect on older recipients. These observations suggest that certain comorbid conditions should be evaluated differently in older patients compared to younger ones.

Increased T cell immunosenescence and accelerated maturation phenotypes in older kidney transplant recipients.

Older kidney transplant recipients experience increased rates of infection and death, and less rejection, compared with younger patients. However, little is known about immune dysfunction in older compared with younger kidney transplant recipients and whether it is associated with infection. We evaluated T cell phenotypes including maturation, immune senescence, and exhaustion in a novel investigation into differences in older compared with younger patients receiving identical immune suppression regimens. We evaluated PBMC from 60 kidney transplant recipients (23 older and 37 matched younger patients) by multiparameter immune phenotyping. Older kidney transplant recipients demonstrated decreased frequency of naïve CD4+ and CD8+ T cells, and increased frequency of terminally differentiated, immune senescent, and NK T cells expressing KLRG1. There was a trend towards increased frequency of T cell immune senescence in patients experiencing infection in the first year after transplantation, which reached statistical significance in a multivariate analysis. This pilot study reveals immune dysfunction in older compared with younger transplant recipients, and suggests a likely mechanism for increased vulnerability to infection. The ability to assess T cell maturation and immune senescence in transplant recipients offers the potential for risk stratification and customization of immune suppression to prevent infection and rejection after transplantation.

Case Report: First Reported Combined Heart-Liver Transplant in a Patient With a Congenital Solitary Kidney.

We report a case of successful combined heart liver transplant in a patient with a congenital solitary kidney. The patient had normal renal function before combined heart-liver transplantation and developed acute kidney injury requiring slow continuous dialysis and subsequent intermittent dialysis for almost 8 weeks post transplantation. Her renal function recovered and she remains off dialysis now 7 months post transplantation. She only currently has mild chronic renal insufficiency. We believe this is the first reported case of successful heart liver transplant in a patient with a congenital solitary kidney.

Novel once-daily extended-release tacrolimus (LCPT) versus twice-daily tacrolimus in de novo kidney transplants: one-year results of Phase III, double-blind, randomized trial.

This Phase III randomized trial examined efficacy and safety of a novel once-daily extended-release tacrolimus formulation (LCP-Tacro [LCPT]) versus twice-daily tacrolimus in de novo kidney transplantation. Primary efficacy end point was proportion of patients with treatment failure (death, graft failure, biopsy-proven acute rejection or lost to follow-up) within 12 months. Starting doses were, LCPT: 0.17 mg/kg/day and tacrolimus twice-daily: 0.1 mg/kg/day; 543 patients were randomized, LCPT: n = 268; tacrolimus twice-daily: n = 275. At 12 months treatment failure was LCPT: 18.3% and tacrolimus twice-daily: 19.6%; the upper 95% CI of the treatment difference was +5.27%, below the predefined +10% noninferiority criteria. There were no significant differences in the incidence of individual efficacy events or adverse events. Target tacrolimus trough levels were more rapidly achieved in the LCPT group. Following initial dose, 36.6% of patients in the LCPT group had rapidly attained trough levels within 6-11 ng/mL versus 18.5% of tacrolimus twice-daily patients; majority of tacrolimus twice-daily patients (74.7%) had troughs <6 ng/mL compared with 33.5% in the LCPT group. Overall, cumulative study dose was 14% lower for LCPT. Results suggest that use of once-daily LCPT in de novo kidney transplantation is efficacious and safe. Lower LCPT dose reflects the improved absorption provided by the novel formulation.

Conversion from twice-daily tacrolimus to once-daily extended release tacrolimus (LCPT): the phase III randomized MELT trial.

Phase III noninferiority trial examining efficacy and safety of converting stable renal transplant recipients from twice-daily tacrolimus to a novel extended-release once-daily tacrolimus formulation (LCPT) with a controlled agglomeration technology. Controls maintained tacrolimus twice daily. The primary efficacy endpoint was proportion of patients with efficacy failures (death, graft failure, locally read biopsy-proven acute rejection [BPAR], or loss to follow-up) within 12 months. Starting LCPT dose was 30% lower (15% for blacks) than preconversion tacrolimus dose; target trough levels were 4-15 ng/mL. A total of 326 patients were randomized; the mITT population (n = 162 each group) was similar demographically in the two groups. Mean daily dose of LCPT was significantly (p < 0.0001) lower than preconversion tacrolimus dose at each visit; mean trough levels between groups were similar. There were four efficacy failures in each group; safety outcomes were similar between groups. Frequency of premature study drug discontinuation was LCPT: 12% versus tacrolimus twice daily: 5% (p = 0.028). LCPT demonstrated noninferiority to tacrolimus twice daily in efficacy failure rates. LCPT may offer a safe and effective alternative for converting patients to a once-daily formulation. Compared to currently available tacrolimus formulation, LCPT requires lower doses to achieve target trough levels.

Associations of pretransplant serum albumin with post-transplant outcomes in kidney transplant recipients.

The association between pretransplant serum albumin concentration and post-transplant outcomes in kidney transplant recipients is unclear. We hypothesized that in transplant-waitlisted hemodialysis patients, lower serum albumin concentrations are associated with worse post-transplant outcomes. Linking the 5-year patient data of a large dialysis organization (DaVita) to the Scientific Registry of Transplant Recipients, we identified 8961 hemodialysis patients who underwent first kidney transplantation. Mortality or graft failure and delayed graft function (DGF) risks were estimated by Cox regression (hazard ratio [HR]) and logistic regression (Odds ratio [OR]), respectively. Patients were 48 ± 13 years old and included 37% women and 27% diabetics. The higher pretransplant serum albumin was associated with lower mortality, graft failure and DGF risk even after multivariate adjustment for case-mix, malnutrition-inflammation complex and transplant related variable. Every 0.2 g/dL higher pretransplant serum albumin concentration was associated with 13% lower all-cause mortality (HR = 0.87 [95% confidence interval: 0.82-0.93]), 17% lower cardiovascular mortality (HR = 0.83[0.74-0.93]), 7% lower combined risk of death or graft failure (HR = 0.93[0.89-0.97]) and 4% lower DGF risk (OR = 0.96[0.93-0.99]). Hence, lower pretransplant serum albumin level is associated with worse post-transplant outcomes. Clinical trials to examine interventions to improve nutritional status in transplant-waitlisted hemodialysis patients and their impacts on post-transplant outcomes are indicated.

Associations of body mass index and weight loss with mortality in transplant-waitlisted maintenance hemodialysis patients.

A body mass index (BMI) below morbid obesity range is often a requirement for kidney transplant wait-listing, but data linking BMI changes to mortality during the waitlist period are lacking. By linking the 6-year (7/2001-6/2007) national databases of a large dialysis organization and the Scientific Registry of Transplant Recipients, we identified 14 632 waitlisted hemodialysis patients without kidney transplantation. Time-dependent survival models examined the mortality predictability of 13-week-averaged BMI, pretransplant serum creatinine as a muscle mass surrogate and their changes over time. The patients were on average 52 ± 13 years old, 40% women and had a BMI of 26.9 ± 6.3 kg/m². Each kg/m² increase of BMI was associated with a death hazard ratio (HR) of 0.96 (95%CI: 0.95-0.97). Compared to the lowest creatinine quintile, the 4th and 5th quintiles had death HRs of 0.75 (0.66-0.86) and 0.57 (0.49-0.66), respectively. Compared to minimal (< ± 1 kg) weight change over 6 months, those with 3 kg- < 5 kg and ≥ 5 kg weight loss had death HRs of 1.31 (1.14-1.52) and 1.51 (1.30-1.75), respectively. Similar associations were observed with creatinine changes over time. Transplant-waitlisted hemodialysis patients with lower BMI or muscle mass and/or unintentional weight or muscle loss have higher mortality in this observational study. Impact of intentional weight change remains unclear.

Outcomes of simultaneous heart-kidney transplant in the US: a retrospective analysis using OPTN/UNOS data.

Simultaneous heart-kidney transplantation (SHK) remains uncommon in the US. We examined outcomes of SHK compared to heart transplant alone (HTA) and deceased donor kidney transplant (DDKT). Data from OPTN/UNOS heart and kidney data bases were used to identify 16,710 HTA, 263 SHK transplants and 68,833 DDK transplants between 1998 and 2007. Outcomes included patient survival (PS), acute cardiac and renal rejection and renal graft survival (rGS). The adjusted risk of death was 44% lower with SHK compared to HTA. Over half of SHK were performed in cases where pretransplant dialysis was not initiated. In these cases, there was no significant difference in the risk of death between SHK and HTA (HR 1.01; 95% CI 0.67-1.50). Recipients of SHK had worse 1-year rGS and PS and had a higher relative risk of overall renal graft loss compared to DDKT recipients. One-year rates of cardiac (14.5%) and renal (6.5%) rejection were lower in SHK compared to HTA and DDKT, respectively. Recipients of SHK had a lower adjusted risk of death compared to HTA recipients, particularly in patients who required pretransplant dialysis. These data suggest that SHK should be considered in heart transplant candidates with renal failure requiring dialysis, whereas the utility of SHK in cases of renal failure not requiring dialysis warrants further study.

Predictive ability of pretransplant comorbidities to predict long-term graft loss and death.

Whether to include additional comorbidities beyond diabetes in future kidney allocation schemes is controversial. We investigated the predictive ability of multiple pretransplant comorbidities for graft and patient survival. We included first-kidney transplant deceased donor recipients if Medicare was the primary payer for at least one year pretransplant. We extracted pretransplant comorbidities from Medicare claims with the Clinical Classifications Software (CCS), Charlson and Elixhauser comorbidities and used Cox regressions for graft loss, death with function (DWF) and death. Four models were compared: (1) Organ Procurement Transplant Network (OPTN) recipient and donor factors, (2) OPTN + CCS, (3) OPTN + Charlson and (4) OPTN + Elixhauser. Patients were censored at 9 years or loss to follow-up. Predictive performance was evaluated with the c-statistic. We examined 25 270 transplants between 1995 and 2002. For graft loss, the predictive value of all models was statistically and practically similar (Model 1: 0.61 [0.60 0.62], Model 2: 0.63 [0.62 0.64], Models 3 and 4: 0.62 [0.61 0.63]). For DWF and death, performance improved to 0.70 and was slightly better with the CCS. Pretransplant comorbidities derived from administrative claims did not identify factors not collected on OPTN that had a significant impact on graft outcome predictions. This has important implications for the revisions to the kidney allocation scheme.

Can machine perfusion decrease the likelihood of discard among biopsied kidneys?

Many factors, such as donor risk factors and renal function, have been shown to be associated with an increased likelihood of discard after recovering kidneys from deceased donors. When these factors are insufficient for assessment, renal biopsy is often performed at the time of harvest to assess suitability. Our aims were to identify factors that predict the discard of a biopsied kidney and to assess the impact of machine perfusion (MP) on kidney discard. We biopsied 678 kidneys from deceased donors aged >or=40 years from 2001 to 2006. We used a logistic regression model to estimate the adjusted odds ratios for kidney discard. Thirty-nine percent (n = 261) of biopsied kidneys were discarded. Kidneys with glomerulosclerosis (GS) > 20% had the highest likelihood of discard. Other significant predictors of discard included extreme donor age, final resistance (>40), atherosclerosis, interstitial fibrosis, arteriolosclerosis, and terminal serum creatinine value (SCr) > 1.5 mg/dL. MP kidneys (n = 69) were less likely to be discarded than cold storage (CS) kidneys after adjusting for other factors (adjusted odds ratio = .13, P < .001). In conclusion, abnormal biopsy findings were associated with the highest likelihood of discard. MP was used in only 10% of the cases; however, the use of MP was associated with a decreased likelihood of discard among biopsied kidneys.

Factors associated with discard of recovered kidneys.

We reviewed diseased donor (DD) kidney usage at a single Organ Procurement Organization in Southern California to more closely examine factors associated with discard. From 2001 to 2006, 3863 kidneys from 1959 DDs were recovered, but 454 (11.8%) were subsequently discarded. Among the discarded kidneys, 211 (46.5%) were discarded based upon biopsy findings, 19 (4.2%) due to anatomical abnormalities, 16 (3.5%) based on donor quality, and 14 (3.1%) because they were felt to be too old to be pumped. Multivariate logistic regression analysis was performed using significant prognostic factors upon univariate analyses. According to the magnitude of the adjusted odds ratio (AOR), significant prognostic factors for discard were extreme donor age (AOR = 24.1 of age 70-80 years, P < .001; AOR = 6.34 age 50-69 years, P < .001; AOR = 2.77 age 40-49 years, P < .001; and AOR = 3.09 age <10 years, P < .001 vs age 10-39 years), high final resistance (AOR = 8.86 of >40 vs others, P = .006), glomerulosclerosis (GS) > 20% (AOR = 5.94 vs GS 0%-5%/no biopsy, P < .001), severe atherosclerosis (AOR = 4.66, P = .003), abnormal anatomy (AOR = 2.7, P < .001), and moderate or severe arteriolosclerosis (AOR = 2.2 vs none/mild/no biopsy, P < .001). Among biopsy findings, the presence of GS > 20% was associated with the highest likelihood of discard. A high final resistance increased the likelihood of discard as well. In conclusion, these findings may help to set the groundwork toward a more uniform approach to organ utilization in donor service areas.

A retrospective analysis of immunosuppression compliance, dose reduction and discontinuation in kidney transplant recipients.

We describe factors associated with poor compliance and dose reductions and examine the relative impact of compliance, dose reduction and discontinuation on graft outcome. Medicare claims for MMF in 7062 deceased donor renal recipients with at least 1 year of graft function were used to calculate compliance and dose reductions. Compliance was modeled using medication possession ratio to define quartiles for poor, low, medium and high compliance. The relative impact of compliance, dose reduction and discontinuation on graft outcome was assessed with Cox proportional hazards. Pediatric (Age 0-18, Odds ratio = 1.71, 95% CI 1.11-2.63, p = 0.014) and adolescent recipients (19-24, 1.57, 1.23-2.00, p < 0.001) were more likely poorly compliant compared to adults age 25-44. Poor compliance was also associated with physical limitations, hypertension, delayed graft function, rejection, infection and GI conditions. Poor (1.43, 1.11-1.84, p = 0.005) and low (1.46, 1.13-1.88, p = 0.004) compliance was associated with an increased hazard of graft loss as was >50% dose reduction (1.69, 1.15-2.50, p = 0.008) and discontinuation (8.34, 6.85-10.2, p < 0.001). Medication possession ratios lower than the 3-year mean were associated with an increased risk of graft loss. These results may indicate that interventions to improve compliance among kidney transplant recipients should strive for high rather than discourage low compliance.

The onset of rapidly progressive neurologic deterioration after a brief gastrointestinal illness in a renal allograft recipient.

Renal transplant recipients are at increased risk for life-threatening complications, most commonly infections. Because of their impaired cell-mediated immunity, these patients are particularly susceptible to organisms that rely on intracellular survival and spread, such as Listeria monocytogenes. Despite being a food-borne pathogen, L. monocytogenes is associated with significant morbidity and mortality. Here we report the case of a renal transplant recipient who developed rapidly progressive neurological symptoms after a brief gastrointestinal illness. Magnetic resonance imaging scan of the brain showed a large mass that was identified as an abscess due to L. monocytogenes. Timely aspiration and antibiotic treatment resulted in complete recovery, as opposed to worse outcomes in the available case reports. We further review the epidemiology, microbiology, clinical presentation, and therapeutic options for listerial brain abscess.

Overview of renal transplantation.

Kidney transplantation is the treatment of choice for end stage renal disease patients. Recent advances, including newer immunosuppressants, revision of organ allocation policies, and better medical care of renal transplant recipients, have resulted in an increase number of transplants with improved outcomes. The major obstacles include the lack of improvement in long term outcomes, shortage of organs and long-term morbidity of candidates with chronic kidney disease. This review highlights transplant immunology, organ allocation, immunosuppressive medications, and complications of transplantation involving post transplantation infections, diabetes, and cardiovascular disease.

Effect of induction therapy protocols on transplant outcomes in crossmatch positive renal allograft recipients desensitized with IVIG.

Here we retrospectively examine the efficacy of two antibody induction regimens using Zenapax or Thymoglobulin in patients with positive complement-dependent cytotoxicity crossmatches (CDC-CMXs) desensitized with IVIG (intravenous immunoglobulin). Between January 1999 and March 2005, 97 patients with (+) CDC-CMXs received kidney transplants (43 deceased donors/54 living donors). All patients received at least 2 g/kg IVIG (maximum four doses) until an acceptable CMX was obtained. Patients were divided into two groups: 1. IVIG + Zenapax (n = 58), 2. IVIG + Thymoglobulin (n = 39). A total of 94% of patients in Group 1 and 84% in G2 have at least 2 years of follow up. Patient and graft survival was 96%/84% in Group 1 and 100%/90% in Group 2, p = NS. The number and severity of AR episodes were similar (36% Group 1 vs. 31% Group 2, p = NS) as was the incidence of C4d (+) antibody-mediated rejection (AMR) (Banff Grade II/III) (22% Group 1 vs. 21% Group 2). Mean serum creatinines (SCrs) at 24 months were similar (Group 1: 1.4 +/- 0.7 vs. G2: 1.5 +/- 0.7 mg/dL). Induction therapy with Zenapax or Thymoglobulin results in excellent patient, graft survival and graft function at 2 years. There was no increased risk of viral infections or malignancies with either agent. Neither agent was effective in reducing the incidence of AMR.

Pulsatile perfusion reduces the incidence of delayed graft function in expanded criteria donor kidney transplantation.

The use of expanded criteria donors (ECD) has been proposed to help combat the discrepancy between organ availability and need. ECD kidneys are associated with delayed graft function (DGF) and worse long-term survival. The aim of this study is to evaluate the impact of pulsatile perfusion (PP) on DGF and graft survival in transplanted ECD kidneys. From January 2000 to December 2003, 4618 ECD kidney-alone transplants were reported to the United Network for Organ Sharing. PP was performed on 912 renal allografts. The prognostic factors of DGF were analyzed using multivariate logistic regression analysis. Risk factors for reduced allograft viability were greater in donors and recipients of PP kidneys. Three-year graft survival of ECD kidneys preserved with PP was similar to cold storage (CS) kidneys. The incidence of DGF in PP kidneys was significantly lower than CS kidneys (26% vs. 36%, p < 0.001). Despite having a greater number of risk factors for reduced graft viability, the ECD-PP kidneys had similar graft survival compared to ECD-CS kidneys. The use of PP, by decreasing the incidence of DGF, may possibly lead to lower overall costs and increased utilization of donor kidneys.

Meta-analysis: the dialysis mode and immunological response to hepatitis B virus vaccine in dialysis population.

BACKGROUND: Patients on maintenance dialysis typically show a suboptimal immune response to hepatitis B virus vaccine compared with the non-uraemic population. Some authors have claimed that dialysis mode has an impact on the immune response to hepatitis B virus vaccine but consistent information is lacking on this issue. AIM: To evaluate the relationship between dialysis mode and immune response to hepatitis B vaccine in dialysis population by performing a systematic review with a meta-analysis of clinical trials. METHOD: We used the random effects model of DerSimonian and Laird; sources of heterogeneity in effect estimates were explored by performing sensitivity analyses. RESULTS: The relative risk of failure to respond to hepatitis B vaccine among patients who underwent maintenance haemodialysis vs. peritoneal dialysis was the end point of interest. We identified 14 clinical trials involving 1211 unique patients on maintenance dialysis. Pooling of study results did not show a significant decreased risk of response to hepatitis B vaccine among haemodialysis patients (overall risk ratio: 1.0, 95% confidence intervals: 0.92-1.1). The P-value was 0.13 for our test of study heterogeneity. CONCLUSION: There is no significant link between dialysis mode and seroresponse to hepatitis B virus vaccine in dialysis population.

Successful use of oral ganciclovir for the treatment of intrauterine cytomegalovirus infection in a renal allograft recipient.

Congenital cytomegalovirus (CMV) infection occurs in approximately 1% of newborns and is the leading infectious cause of congenital birth defects. Female renal allograft recipients who develop CMV infection during pregnancy are at risk for both graft dysfunction and fetal morbidity. DNA-based analysis of amniotic fluid (AF) from at-risk pregnancies has been suggested as an adjunct/substitute for traditional culture. We have shown that CMV-polymerase chain reaction of AF is a useful diagnostic test for congenital CMV infection. Using this test we diagnosed CMV infection in the fetus of a 30-year-old renal transplant recipient. As termination was not an option for the family, the patient was extensively counseled and treated with oral ganciclovir. This resulted in clearance of the virus from the AF and the delivery of a healthy newborn girl, free of CMV disease. This is the first reported case to our knowledge of successful use of maternal ganciclovir to treat intrauterine CMV infection in a pregnant renal transplant recipient.

Lamivudine in the treatment of HBV-related liver disease after renal transplantation: an update.

Diminished survival due to hepatitis B has been observed after renal transplantation (RT). Lamivudine, a second-generation nucleoside analogue, has been approved for the treatment of chronic hepatitis B virus (HBV) infection in patients with normal renal function. Numerous clinical experiences with lamivudine after RT have been recently published. Despite numerous shortcomings, all of these reports have shown encouraging results. The rate of clearance of HBV viremia ranged between 67% and 100%, and the frequency of ALT normalization was between 50% and 100% with lamivudine use. Even patients with fibrosing cholestatic hepatitis, a serious form of HBV-related liver disease with ominous course, have been successfully treated with lamivudine. Lamivudine therapy significantly improved the survival of HBsAg positive renal allograft recipients. However, numerous issues concerning the treatment of hepatitis B after RT remain unclear: the optimal time to initiate lamivudine, the appropriate duration of antiviral therapy after RT, and the role for pre-transplantation liver biopsy. Also, the management of lamivudine resistance remains a concern for physicians. Clinical trials are under way.