Miguel S. West

Infectious complications after kidney transplantation: current epidemiology and associated risk factors

Abstract:  Background:  The impact of newer immunosuppressive and antimicrobial prophylactic agents on the pattern of infectious complications following kidney transplantation has not been well studied.

Preliminary Experience With Cinacalcet Use in Persistent Secondary Hyperparathyroidism After Kidney Transplantation

Background. There is limited experience with the use of cinacalcet in the treatment of persistent secondary hyperparathyroidism after kidney transplantation. Methods. We retrospectively analyzed our experience in 18 renal allograft recipients who initiated cinacalcet therapy from 1 month to 23 years (median 3 years) posttransplantation and were maintained on the drug for 6 months. The daily dose was titrated from 30 mg up to a maximum of 180 mg to achieve a reduction in serum intact parathyroid hormone (PTH) levels. Results. Sustainable, significant decreases in mean calcium and alkaline phosphatase were noted at 1 month and intact PTH by 3 months, with 50% of patients achieving at least a 30% drop in PTH levels at 6 months. Serum phosphorous increased at 6 months, whereas urine N-telopeptides decreased. There were no significant changes in serum osteocalcin, albumin, and hemoglobin levels. We did not observe a tachyphylaxis phenomenon. Two patients reported occasional nausea, but did not require medication discontinuation. Estimated glomerular filtration rate did decrease progressively over the 6-month period. Conclusion. Cinacalcet appears to be an effective drug for the treatment of posttransplant hypercalcemia due to persistent secondary hyperparathyroidism. Further studies with more patients and longer follow-up will be needed to better elucidate the efficacy/safety profile for this agent, particularly with regard to long-term bone histology and renal outcomes.

Induction therapy with basiliximab versus thymoglobulin in african-american kidney transplant recipients

Background. It has been suggested that the use of antilymphocyte induction therapy in African-American (AA) renal transplant recipients reduces the risk of acute rejection (AR) and improves graft survival. It is not clear whether the efficacy of basiliximab (BSX) is different from that of Thymoglobulin (ATG) in this regard. Methods. We retrospectively assessed the effect of induction therapy with BSX versus ATG in 88 AA renal allograft recipients receiving transplants at our center between July 2001 and June 2003 and followed for 19±7 months. All patients were maintained on mycophenolate mofetil, prednisone, and either tacrolimus or sirolimus. Study endpoints included patient and graft survival, graft function, and incidence of AR and cytomegalovirus infection. Regression models were used to evaluate the independent effect of each induction agent on these endpoints. Results. Thirty-six patients received ATG, and 52 received BSX. The groups were comparable with regard to donor race and age, and recipient sex, body mass index, human leukocyte antigen (HLA) matching, and hepatitis C virus serostatus. The ATG group was younger, more likely to receive retransplant, had longer duration of end-stage renal disease and higher panel reactive antibody, and was less likely to receive live-donor organs. However, after adjusting for all these variables, graft outcomes, as well as renal function, were comparable between the two induction groups. We found that the degree of HLA mismatch, delayed graft function, and AR were the only significant predictors of graft loss. Conclusion. The results of our study suggest that the choice of induction agent may not have a major impact on graft outcomes in AA renal-allograft recipients.

Preliminary experience with renal transplantation in HIV+ recipients: low acute rejection and infection rates.

Background. Only four centers have reported their results with renal transplantation in human immunodeficiency virus (HIV)+ recipients on highly active antiretroviral therapy, and acute rejection (AR) rates have consistently ranged from 43% to 67%. Methods. We examined the outcomes of eight adult HIV+ primary renal allograft recipients with median 15 (range 8–47) months follow-up with multiple other high-risk factors, including African American ethnicity, hepatitis C virus (HCV) positivity, long waiting times, prior sensitization, paucity of live donors, and delayed graft function. Our immunosuppressive protocol consisted of an anti-interleukin-2 receptor antibody for induction, and mycophenolate mofetil, cyclosporin A, and prednisone for maintenance. Initial and 3- to 6-month cyclosporin A trough level targets were 250 to 300 and 225 to 275 ng/mL, respectively, and mycophenolate mofetil dose was adjusted according to 2 to 4 week surveillance and subsequent as needed mycophenolic acid predose concentrations during the first 6 months. Results. Patient and graft survival were 100% and 88%, respectively, with an AR rate of 13% and excellent renal function. No patients developed new-onset diabetes, opportunistic or other serious infections, malignancy, or progression of hepatitis C virus-related liver disease. Excellent suppression of HIV replication with maintenance of CD4 counts was noted in all cases. Conclusions. Our findings suggest that HIV+ patients on highly active antiretroviral therapy can undergo successful renal transplantation with a low incidence of both AR and AIDS-associated and non-AIDS associated infections, despite associated risk factors for poorer outcome. Our encouraging but preliminary results with this protocol will need to be verified in larger numbers of HIV+ renal allograft recipients with longer follow-up.

Short‐Term Experience with Early Steroid Withdrawal in African‐American Renal Transplant Recipients

There are limited data on the results of early steroid withdrawal (ESW) in African‐American (AA) renal allograft recipients. We examined short‐term transplant outcomes in a retrospective, non‐concurrent cohort study of 40 AAs who did not (ESW group), and 33 who did [steroid maintenance (SM) group] receive maintenance steroids after day 4 post‐transplant. Patients received thymoglobulin (ATG) induction, mycophenolate mofetil, and tacrolimus or sirolimus. Data were analyzed using survival analysis methods and regression models. Patients in the ESW group were older, had lower current panel reactive antibody and fewer re‐transplants, and received fewer doses of ATG. One‐year graft survival and acute rejection (AR) rates were 100% and 13% in the ESW group and 97% and 15% in the SM group. After controlling for confounders, at 1 year, ESW was not associated with higher risk of graft loss, AR, or worse graft function, but was associated with less weight gain. The SM group had higher cholesterol levels at 3 months and higher risk of post‐transplant diabetes mellitus. We did not observe any cases of subclinical rejection. This study suggests that ESW under modern immunosuppression is safe over the short term in at least a subset of AA recipients with risk profiles similar to those studied herein, and could be associated with improved outcomes.

Sirolimus‐Induced Angioedema

Sirolimus (SRL) is a macrolide immunosuppressant that has gained widespread use in organ transplantation. Its full spectrum of side‐effects is yet to be defined. We describe herein three cases of SRL‐induced angioedema (AE) in African‐American (AA) primary renal allograft recipients who received SRL in combination with mycophenolate mofetil and steroids. In two cases, AE manifested after SRL was restarted after a period of discontinuation. The third case presented upon initial exposure to the drug. None of the patients was receiving any drug that has been previously associated with AE. Complete resolution occurred only after SRL was withdrawn. AE has not recurred in any of the patients during a follow‐up period of up to 21 months. We conclude that AE is a previously unrecognized adverse event associated with SRL use. Close monitoring for this side‐effect, especially in AA patients, is warranted.

Intravenous immunoglobulin, HLA allele typing and HLAMatchmaker facilitate successful transplantation in highly sensitized pediatric renal allograft recipients

Abstract:  The use of intravenous immunoglobulin (IVIG) in sensitized transplant candidates has resulted in reduced HLA antibody levels and shorter transplant wait times. In addition, the HLAMatchmaker program has been used to identify acceptable mismatches to permit transplantation in highly sensitized patients. We used IVIG desensitization in conjunction with high resolution HLA allele typing and HLAMatchmaker grading of donor offers to facilitate successful transplantation in two highly sensitized children who were awaiting second renal transplants. Both patients lost their initial transplant in <10 days to accelerated acute rejection, and were on dialysis for an average of 50 months with high panel reactive antibody (PRA) levels. They were started on monthly IVIG infusions (2 g/kg/dose). Within one wk following their third and fifth IVIG doses, both patients received a crossmatch compatible, deceased donor renal transplant selected by HLAMatchmaker as a suitable donor offer. Both patients remain rejection free with excellent renal function 19 and 15 months post‐transplant, respectively. In conclusion, combining IVIG therapy and donor selection by HLA humoral epitope matching permitted successful transplantation of two highly sensitized children. Further studies in larger numbers of patients with longer follow‐up are needed to determine the individual role played by, and relative importance of each component of this combined strategy.

Sirolimus exposure during the early post‐transplant period reduces the risk of CMV infection relative to tacrolimus in renal allograft recipients

Abstract:  Introduction:  There are limited data regarding the role of individual maintenance immunosuppressive agents in the development of cytomegalovirus (CMV) infection. We examined the association between exposure to sirolimus (SRL) and risk of CMV infection after kidney transplantation when compared with tacrolimus (TCL).

West Nile virus encephalitis: an emerging disease in renal transplant recipients.

Abstract:  West Nile virus (WNV) has emerged as an important cause of several outbreaks of febrile illness and encephalitis in North America over the past few years. The most common manifestation in symptomatic patients is a transient febrile illness. Neuroinvasive disease, that can be fatal, occurs most often in elderly and immunocompromised hosts. The role of this virus as a cause of meninoencephalitis in organ transplant recipients is becoming better recognized. We describe herein the clinical course of two renal allograft recipients who developed WNV encephalitis. One patient developed status epilepticus and eventually died, while the other had a full recovery. In both cases, the diagnosis was confirmed by detection of WNV‐specific IgM in CSF or serum, with a delayed antibody response in one patient. This viral infection should be considered in all renal transplant recipients who present with a febrile illness associated with neurological symptoms.

Predictive value of human leucocyte antigen epitope matching using HLAMatchmaker for graft outcomes in a predominantly African-American renal transplant cohort.

Abstract: The HLAMatchmaker program is based on the donor/recipient comparison of the polymorphic triplet amino‐acid sequences of the antibody‐accessible regions on the human leucocyte antigen (HLA) molecule. The previous reports on its predictive value for renal allograft outcomes are conflicting. We conducted a retrospective study in a predominantly African‐American (AA) cohort (N=101, 94% AA). HLA typing was performed by molecular methods and triplet matching using HLAMatchmaker. Study end points included graft survival and incidence of acute rejection. The relationship between the number of triplet mismatches (TMM) and the degree of HLA antigen MM was evaluated using Pearsons correlation coefficient. Logistic regression models were used to examine the association between triplet matching and the study end points. Kaplan–Meier and Cox proportional hazard models were used for graft survival analysis. The strongest relationship between the number of TMM and HLA antigen MM was observed for HLA‐DQ (r=0.88). The association between triplet matching at HLA‐A, ‐B, ‐DR and ‐DRw HLA loci and the study end points was not statistically significant. However, after grouping, the unadjusted estimates of graft survival for those with more than 10 Class I TMM were significantly worse than the others (p=0.03). Adjusting for the effect of donor source, recipient characteristics and the immunosuppressive regimen did not change this association (hazard ratio=0.2, confidence interval=0.04–1.1). We conclude that triplet matching using HLAMatchmaker can provide useful prognostic information in kidney transplantation and that more than 10 donor/recipient Class I HLA TMM is predictive of worse graft outcome.