Sayeed K. Malek

The combination of donor and recipient age is critical in determining host immunoresponsiveness and renal transplant outcome.

Objective:To evaluate the interaction of donor and recipient age on transplant outcome and immune response. Summary Background Data:The age of donor and recipient is becoming increasingly important in organ transplantation. We tested the relevance and consequences of recipient and donor age on immunoresponsiveness and transplant outcome in a uni- and multilateral cohort analysis. Methods:We obtained and analyzed data from 108,188 recipients of deceased donor kidneys of the United Network for Organ Sharing database transplanted between 1995 and 2008. Univariate analysis of allograft and patient survival was calculated by Kaplan Meyer. Multivariate analyses were performed using the Cox Proportional Hazards method. Data were assessed and compared by decades of increasing donor and recipient age with and without censoring transplant loss for death with a functioning graft. This approach allowed a detailed analysis of interacting factors. Results:Transplant survival was lowest in elderly recipients. However, when the analysis was censored for patients death with a functioning kidney transplant, survival improved incrementally with each decade of increasing recipient age. This was even more surprising as older recipients had received less well-matched organs of poorer quality. The frequency of acute rejection decreased dramatically with increasing age, emphasizing the effect of age on the vigor of the recipients immune responses. In contrast, increasing donor age was associated with more frequent acute rejection rates. The effects of donor and recipient age in combination demonstrated that grafts of older donors fared significantly better in older recipients. Conclusions:Our results show that increasing recipient age is associated with an improved transplant survival, lower rates of rejection, and superior outcome of older donor organs. Physiological and/or immunologic aspects of organ and recipient age seem to determine, at least in part, the success of renal transplantation.

Evaluation of fluoroquinolones for the prevention of BK viremia after renal transplantation.

BACKGROUND AND OBJECTIVES Nearly 30% of renal transplant recipients develops BK viremia, a prerequisite for BK nephropathy. Case reports have evaluated treatment options for BK virus, but no controlled studies have assessed prophylactic therapies. Fluoroquinolone antibiotics were studied for prevention of BK viremia after renal transplantation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This retrospective analysis evaluated adult renal transplant recipients with at least one BK viral load (blood) between 90 and 400 days after transplantation. Six to 12 months of co-trimoxazole was used for Pneumocystis prophylaxis. In sulfa-allergic/-intolerant patients, 6 to 12 months of atovaquone with 1 month of a fluoroquinolone was used. Fluoroquinolones can inhibit BK DNA topoisomerase. The two groups studied were those that received 30 days of levofloxacin or ciprofloxacin after transplantation and those that did not. The primary endpoint was BK viremia rates at 1 year. Of note, of the 160 patients not receiving fluoroquinolone prophylaxis, 40 received a fluoroquinolone for treatment of a bacterial infection within 3 months after transplantation. Subgroup analysis evaluating these 40 patients against the 120 who had no exposure to fluoroquinolones was completed. RESULTS A 1-month fluoroquinolone course after transplantation was associated with significantly lower rates of BK viremia at 1 year compared with those with no fluoroquinolone. In the subgroup analysis, exposure to fluoroquinolone for treatment of bacterial infections within 3 months after transplantation was associated with significantly lower 1-year rates of BK viremia. CONCLUSIONS This analysis demonstrates that fluoroquinolones are effective at preventing BK viremia after renal transplantation.

Donor postextubation hypotension and age correlate with outcome after donation after cardiac death transplantation.

Background. Compared with standard donors, kidneys recovered from donors after cardiac death (DCD) exhibit higher rates of delayed graft function (DGF), and DCD livers demonstrate higher rates of biliary ischemia, graft loss, and worse patient survival. Current practice limits the use of these organs based on time from donor extubation to asystole, but data to support this is incomplete. We hypothesized that donor postextubation parameters, including duration and severity of hemodynamic instability or hypoxia might be a better predictor of subsequent graft function. Methods. We performed a retrospective examination of the New England Organ Bank DCD database, concentrating on donor factors including vital signs after withdrawal of support. Results. Prolonged, severe hypotension in the postextubation period was a better predictor of subsequent organ function that time from extubation to asystole. For DCD kidneys, this manifested as a trend toward increased DGF. For DCD livers, this manifested as increased rates of poor outcomes. Maximizing the predictive value of this test in the liver cohort suggested that greater than 15 min between the time when the donor systolic blood pressure drops below 50 mm Hg and flush correlates with increased rates of diffuse biliary ischemia, graft loss, or death. Donor age also correlated with worse outcome. Conclusions. Time between profound instability and cold perfusion is a better predictor of outcome than time from extubation to asystole. If validated, this information could be used to predict DGF after DCD renal transplant and improve outcomes after DCD liver transplant.

Campath-1H induction and the incidence of infectious complications in adult renal transplantation.

Background. The purpose of this study was to evaluate adult renal transplantation patients who received a alemtuzumab (Campath-1H)-based induction protocol for the incidence of infectious complications. Methods. We began using 30 mg Campath-1H intravenously for induction therapy in May 2003. The patients were treated with a maintenance regimen of tacrolimus or mycophenolate mofetil (MMF), and rapidly tapered prednisone; valganciclovir was used for CMV prophylaxis. Forty-nine adult patients who received renal transplants between May 1, 2003 and June 7, 2004 were included. The mean follow-up time was 13.7 months with a range of 10-24 months. Data were collected via a retrospective chart review. Results. The infectious complications noted in the Campath-1H group were compared with a historical group of 56 patients receiving conventional immunosuppression. There was one case of cytomegalovirus (CMV) viremia and two cases of CMV disease (one pneumonitis and one enteritis). There were four cases of urinary tract infection and one extremity cellulitis. One patient developed Cryptococcal meningitis. Eight of the 49 (16%) patients in the Campath group had an infectious complication, compared to 18 out of 56 (32%) in the historical group. Conclusion. Campath-1H induction for renal transplantation appears to have a low incidence of associated infectious complications when compared to historical regimens.

Initial experience using histidine-tryptophan-ketoglutarate solution in clinical pancreas transplantation.

Abstract:  Background:  The colloid‐based University of Wisconsin (UW) preservation solution has been used extensively in clinical pancreas transplantation. Experimental studies support the use of the crystalloid‐based histidine‐tryptophan‐ketoglutarate (HTK) preservation solution for this purpose.

Racial and ethnic disparities in kidney transplantation

Success of renal transplantation, as a viable alternative to dialysis, has been tempered by long‐standing racial disparities. Ethnic minorities have less access to transplantation, are less likely to be listed for transplantation, and experience a higher rate of graft failure. Reasons for the existing racial disparities at various stages of the transplantation process are complex and multi‐factorial. They include a combination of behavioral, social, environmental, and occupational factors, as well as potential intended or unintended discrimination within the healthcare system. Immunologic factors such as human leukocyte antigen matching, composition of the organ donor pool, and patient immune response, all of which affect post‐transplantation graft rejection rates and patient survival, also contribute to health disparities between ethnic groups.

Renal Transplantation in Patients With Positive Lymphocytotoxicity Crossmatches : One Center's Experience

Background. Sensitization to human leukocyte antigens remains an important barrier to successful renal transplantation. Materials and Methods. Herein we describe our center’s experience with a plasmapheresis-based desensitization protocol for highly sensitized patients. Twenty-nine patients had a positive T-cell or positive B-cell lymphocytotoxicity crossmatch against their donors. In some cases, baseline crossmatches were of high titer (e.g., 11 had baseline titers ≥1:32). Results. Twenty-eight of 29 patients were rendered T-cell crossmatch negative and B-cell crossmatch negative/low positive and transplanted. None had hyperacute rejection but 11 (39%) had acute antibody mediated rejection. Median follow-up is 22 months: 25 of the 28 (89%) of allografts are still functioning with mean plasma creatinine 1.5 mg/dL. There was one death because of the transplant or immunsuppression, one case of cytomegalovirus disease and no cases of lymphoproliferative disease. Conclusion. This series provides further evidence of the high efficacy of plasmapheresis-based desensitization protocols. Even patients with high baseline crossmatch titers can be successfully desensitized and transplanted. Short- and medium-term outcomes are encouraging but longer-term data are needed.

Long-term outcomes of kidney transplantation across a positive complement-dependent cytotoxicity crossmatch.

Background More than 30% of potential kidney transplant recipients have pre-existing anti–human leukocyte antigen antibodies. This subgroup has significantly lower transplant rates and increased mortality. Desensitization has become an important tool to overcome this immunological barrier. However, limited data is available regarding long-term outcomes, in particular for the highest risk group with a positive complement-dependent cytotoxicity crossmatch (CDC XM) before desensitization. Methods Between 2002 and 2010, 39 patients underwent living-kidney transplantation across a positive CDC XM against their donors at our center. The desensitization protocol involved pretransplant immunosuppression, plasmapheresis, and low-dose intravenous immunoglobulin±rituximab. Measured outcomes included patient survival, graft survival, renal function, rates of rejection, infection, and malignancy. Results The mean and median follow-up was 5.2 years. Patient survival was 95% at 1 year, 95% at 3 years, and 86% at 5 years. Death-censored graft survival was 94% at 1 year, 88% at 3 years, and 84% at 5 years. Uncensored graft survival was 87% at 1 year, 79% at 3 years, and 72% at 5 years. Twenty-four subjects (61%) developed acute antibody-mediated rejection of the allograft and one patient lost her graft because of hyperacute rejection. Infectious complications included pneumonia (17%), BK nephropathy (10%), and CMV disease (5%). Skin cancer was the most prevalent malignancy in 10% of patients. There were no cases of lymphoproliferative disorder. Mean serum creatinine was 1.7±1 mg/dL in functioning grafts at 5 years after transplantation. Conclusion Despite high rates of early rejection, desensitization in living-kidney transplantation results in acceptable 5-year patient and graft survival rates.

Acute cellular rejection predominated by monocytes is a severe form of rejection in human renal recipients with or without Campath-1H (alemtuzumab) induction therapy

Campath‐1H has been used successfully for induction and has resulted in a low rate of acute cellular rejection (ACR) in renal transplantation in combination with various postoperative immunosuppression regimens. This study was undertaken to investigate the extent of monocyte involvement in ACR, with or without Campath‐1H induction. We found that monocytes represented the majority of inflammatory cells in grades Ib or higher ACR, but not with Ia type of ACR, regardless of the status of Campath‐1H induction. Cases of ACR, following Campath‐1H induction, appear to demonstrate a ‘pure form’ of monocytic ACR, whereas monocytes were mixed with many other types of inflammatory cells in the cases of ACR in the absence of Campath‐1H induction. In addition with Campath‐1H induction, the cases of monocyte‐predominant ACR were found to uniformly exhibit a good response to corticosteroid treatment. We conclude that monocyte‐predominate ACR may represent a severe form of rejection, with or without Campath‐1H treatment.

The combined risk of donor quality and recipient age: higher-quality kidneys may not always improve patient and graft survival.

Background The Kidney Donor Profile Index (KDPI) is a more precise donor organ quality metric replacing age-based characterization of donor risk. Little prior attention has been paid on the outcomes of lower-quality kidneys transplanted into elderly recipients. Although we have previously shown that immunological risks associated with older organs are attenuated by advanced recipient age, it remains unknown whether risks associated with lower-quality KDPI organs are similarly reduced in older recipients. Methods Donor organ quality as measured by the KDPI was divided into quintiles (very high, high, medium, low, and very low quality), and Cox proportional hazards was used to assess graft and recipient survival in first-time adult deceased donor transplant recipients by recipient age. Results In uncensored graft survival analysis, recipients older than 69 years had demonstrated comparable outcomes if they received low-quality kidneys compared to medium-quality kidneys. Death-censored analysis demonstrated no increased relative risk when low-quality kidneys were transplanted into recipients aged 70 to 79 years (hazard ratio [HR], 1.11; P=0.19) or older than 79 years (HR, 1.08; P=0.59). In overall survival analysis, elderly recipients gained no relative benefit from medium-quality kidneys over low-quality kidneys (70–79 years: HR, 1.03, P=0.51; >79 years: HR, 1.08; P=0.32). Conclusion Our analysis demonstrates that transplanting medium-quality kidneys into elderly recipients does not provide significant advantage over low-quality kidneys.