Jennifer S. Singer

Sirolimus-associated pulmonary toxicity

Background. Pulmonary toxicity has recently been recognized as a potentially serious complication associated with sirolimus therapy. We further detail this condition on the basis of our own cases and those reported in the literature. Methods. We report three cases of suspected sirolimus-induced pulmonary toxicity that occurred in three renal transplant recipients and searched PubMed for all previously reported cases. Results. Including our current cases, 43 patients with sirolimus-induced pulmonary toxicity have now been reported. Clinical data were incomplete in 28 cases. Analysis of available data for 15 patients revealed that the most commonly presenting symptoms were dyspnea on exertion and dry cough followed by fatigue and fever. Chest radiographs and high-resolution computed tomography scans commonly revealed bilateral patchy or diffuse alveolo-interstitial infiltrates. Bronchoalveolar fluid analysis and lung biopsy in selected case reports revealed several distinct histologic features, including lymphocytic alveolitis, lymphocytic interstitial pneumonitis, bronchoalveolar obliterans organizing pneumonia, focal fibrosis, pulmonary alveolar hemorrhage, or a combination thereof. The diagnosis of sirolimus-associated pulmonary toxicity was made after an exhaustive work-up to exclude infectious causes and other pulmonary disease. Sirolimus discontinuation or dose reduction resulted in clinical and radiologic improvement in all 15 patients within 3 weeks. Conclusion. The temporal relationship between sirolimus exposure and onset of pulmonary symptoms in the absence of infectious causes and other alternative pulmonary disease and the associated clinical and radiologic improvement after its cessation suggests a causal relationship. Because the use of sirolimus in organ transplantation has become more widespread, clinicians must remain vigilant to its potential pulmonary complication.

Obesity and outcome following renal transplantation

Single institution series have demonstrated that obese patients have higher rates of wound infection and delayed graft function (DGF), but similar rates of graft survival. We used UNOS data to determine whether obesity affects outcome following renal transplantation.

Preoperative factors associated with outcome and their impact on resource use in 1148 consecutive primary liver transplants.

BACKGROUND Hepatic transplantation is a highly effective but costly treatment for end-stage hepatic dysfunction. One approach to improve efficiency in the use of scarce organs for transplantation is to identify preoperative factors that are associated with poor outcome posttransplantation. This may assist both in selecting patients optimal for transplantation and in identifying strategies to improve survival. METHODS In the present work, we retrospectively reviewed consecutive liver transplants performed at the University of California at Los Angeles during a 6-year period and determined preoperative variables that were associated with outcome in primary grafts. In addition, we used the hospitals cost accounting database to determine the impact of these variables on the degree of resource use by high-risk patients. RESULTS We found five variables to have independent prognostic value in predicting graft survival after primary liver transplantation: (1) donor age, (2) recipient age, (3) donor sodium, (4) recipient creatinine, and (5) recipient ventilator requirement pretransplant. Recipient ventilator requirement and elevated creatinine were associated with significant increases in resource use during the transplant admission. CONCLUSIONS Patients at high risk for graft failure and costly transplants can be identified preoperatively by a set of parameters that are readily available, noninvasive, and inexpensive. Selection of recipients on the basis of these data would improve the efficiency of liver transplantation and reduce its cost.

Disparities in the Utilization of Live Donor Renal Transplantation

Despite universal payer coverage with Medicare, sociodemographic disparities confound the care of patients with renal failure. We sought to determine whether adults who realize access to kidney transplantation suffer inequities in the utilization of live donor renal transplantation (LDRT). We identified adults undergoing primary renal transplantation in 2004–2006 from the United Network for Organ Sharing (UNOS). We modeled receipt of live versus deceased donor renal transplant on multilevel multivariate models that examined recipient, center and UNOS region‐specific covariates. Among 41 090 adult recipients identified, 39% underwent LDRT. On multivariate analysis, older recipients (OR 0.62, 95% CI 0.56–0.68 for 50–59 year‐olds vs. 18–39 year‐old recipients), those of African American ethnicity (OR 0.54, 95% CI 0.50–0.59 vs. whites) and of lower socioeconomic status (OR 0.72, 95% CI 0.67–0.79 for high school‐educated vs. college‐educated recipients; OR 0.78, 95% CI 0.71–0.87 for lowest vs. highest income quartile) had lower odds of LDRT. These characteristics accounted for 14.2% of the variation in LDRT, more than recipient clinical variables, transplant center characteristics and UNOS region level variation. We identified significant racial and socioeconomic disparities in the utilization of LDRT. Educational initiatives and dissemination of processes that enable increased utilization of LDRT may address these disparities.

Predictors and Risk Factors for Recurrent Scleroderma Renal Crisis in the Kidney Allograft: Case Report and Review of the Literature

Scleroderma renal crisis (SRC) can lead to end‐stage renal disease (ESRD) and subsequent need for dialysis and/or renal transplantation. We review all reported cases of renal transplantations in scleroderma patients from PubMed search, present UNOS data on transplant outcomes, and identify predictors for allograft SRC. Of the five cases with recurrent SRC, all developed ESRD within a year of onset of native kidney SRC, whereas none of those who developed ESRD more than 1–2 years after the onset of SRC developed recurrence. Anemia preceded allograft SRC in two cases, pericardial effusion in one, and skin tightening in two others. UNOS data (October 1987–July 2004) documented 260 transplants performed for the renal diagnosis of scleroderma, with a 5‐year graft survival rate of 56.7%. The risk for allograft SRC recurrence appears to correlate with early native renal function loss following the onset of SRC. Recurrent SRC in the allograft may be heralded by multiple clinical markers known to be predictive of severe scleroderma, including progression of diffuse skin thickening, new‐onset anemia and cardiac complications.

A comparative study of Merkel cell, BK and JC polyomavirus infections in renal transplant recipients and healthy subjects.

BACKGROUND Merkel cell carcinoma (MCC) is a rare skin cancer associated with immunosuppression and the integration of Merkel cell polyomavirus (MCPyV) DNA into the tumor cell genome. Little is known about the natural history of MCPyV infection. OBJECTIVES To investigate the presence of MCPyV, BK and JC polyomaviruses in serum and urine from immunosuppressed kidney transplant patients (KTx) and a control group of normal volunteers. STUDY DESIGN Quantitative real-time PCR (q-PCR) was used to assess MCPyV, BKV and JCV viral load in urine and serum samples collected from normal donors (Group A), prospectively enrolled KTx patients (Group B) and from KTx with documented BK reactivation and/or nephropathy (Group C). RESULTS Low levels of MCPyV viruria was seen in 15% of the subjects in Group A, 30% of Group B, and was not detected in Group C. No individuals in the study developed MCPyV viremia. BK viruria was seen in 5% of Group A, 30% of Group B, and 100% of Group C. Consistent with previous reports, the mean BKV urinary load was significantly higher in immunosuppressed patients compared to non-immunosuppressed controls and also higher in urine compared to serum samples. CONCLUSIONS Like BKV and JCV, MCPyV is likely a common infection in adult humans. Low level shedding of MCPyV in urine was similar in immunosuppressed organ transplant recipients to non-immunosuppressed subjects. However, MCPyV was not detected and JCV was infrequent in samples from KTx patients with clinical BKV reactivation.

Operative parameters that predict the outcomes of hepatic transplantation

BACKGROUND A growing discrepancy between the number of patients awaiting liver transplantation and the number of organs available mandates the use of even marginal organ donors in whom there is major risk of suboptimal graft function. A comprehensive analysis of operative parameters on the outcomes of liver transplantation has not been reported. STUDY DESIGN We analyzed the impact of 24 operative variables on the survival of 942 consecutive primary liver allografts performed at a single center from June 1992 through December 1997. Univariate and Cox proportional hazards analysis was used to identify those variables with independent prognostic significance in graft survival. Resource utilization for variables with multivariate significance was also analyzed. RESULTS Of 12 intraoperative variables found to have significance in univariate analysis, three were significant by Cox multivariate analysis: 1) lack of immediate bile production by the graft intraoperatively, 2) platelet transfusion > or = 20 U, and 3) recipient urine output < or =2.0 mL/kg/h intraoperatively. Each of the three variables was associated with marked increases in hospital and Intensive Care Unit length of stay and hospital charges accrued during the admission for transplantation. CONCLUSION We identified three operative parameters that predict a poor outcome after liver transplantation. The presence of these indicators suggests that early retransplantation should be considered. Early identification of grafts likely to have poor function might also provide an opportunity for therapeutic intervention to salvage graft function.

Laparoscopic Versus Open Renal Procurement for Pediatric Recipients of Living Donor Renal Transplantation

Despite reports demonstrating the safety of laparoscopic donor nephrectomy (LDN) for pediatric recipients of renal transplants, recent evidence has challenged using LDN for recipients 5 years of age or younger.

Readability of Health Related Quality of Life Instruments in Urology

PURPOSE The average American adult reads at a fifth to eighth-grade level, with wide variability, presenting challenges for the assessment of self-reported health related quality of life. We identified the health related quality of life instruments used in patients with urological diseases and evaluated their readability. MATERIALS AND METHODS We focused on the most burdensome urological diseases, based on total expenditures in the United States. We then identified disease specific instruments by systematically searching PubMed, the Cochrane Database of Systematic Reviews, Google, Google Scholar, the Patient Reported Outcome and Quality of Life Instruments Database (Mapi Research Institute, Lyon, France) and Yahoo! for health related quality of life studies in patients with these urological conditions. Where disease specific instruments were lacking, we noted the general health related quality of life measures most commonly used. For each instrument, we calculated the median Flesch-Kincaid grade level, the proportion of questionnaire items below an eighth-grade reading level, the mean Flesch Reading Ease, and the mean number of words per sentence and characters per word, all of which are validated measures of readability. RESULTS The average +/- SD of the median Flesh-Kincaid reading levels was 6.5 +/- 2.1 (range 1.0 to 12.0). Of the 76 instruments 61 (80%) were at or below an eighth-grade reading level. The mean reading ease was greater than 30 for each of the 76 questionnaires and greater than 60 for 66 (87%). Urinary tract infection, the costliest urological disease, has only 1 disease specific health related quality of life measure. Urolithiasis, the second costliest, has none. CONCLUSIONS The reading level of health related quality of life questionnaires in urology is appropriate for the reading ability of most adults in the United States. However, the most burdensome urological diseases lack disease specific health related quality of life instruments.

Allochimeric class I MHC molecules prevent chronic rejection and attenuate alloantibody responses

BACKGROUND We have shown that treatment with molecularly engineered, allochimeric [alpha1 hl/u]-RT1.Aa class I MHC antigens bearing donor-type Wistar-Furth (WF, RT1.Au) amino acid substitutions for host-type ACI (RTI.Aa) sequences in the alpha1-helical region induces donor-specific tolerance to cardiac allografts in rat recipients. This study examined the effect of allochimeric molecules on the development of chronic rejection. METHODS Allochimeric [alpha1 hl/u]-RT1.Aa class I MHC antigenic extracts (1 mg) were administered via the portal vein into ACI recipients of WF hearts on the day of transplantation in conjunction with subtherapeutic oral cyclosporine (CsA, 10 mg/kg/day, days 0-2). Control groups included recipients of syngeneic grafts and ACI recipients of WF heart allografts treated with high-dose CsA (10 mg/kg/day, days 0-6). RESULTS WF hearts in ACI rats receiving 7 days of CsA exhibited myocardial fibrosis, perivascular inflammation, and intimal hyperplasia at day 80. At day 120, these grafts displayed severe chronic rejection with global architectural disorganization, ventricular fibrosis, intimal hyperplasia, and progressive luminal narrowing. In contrast, WF hearts in rats treated with [alpha1 hl/u]-RT1.Aa molecules revealed only mild perivascular fibrosis, minimal intimal thickening, and preserved myocardial architecture. Alloantibody analysis demonstrated no IgM alloantibodies in all groups. An attenuated, but detectable, anti-WF IgG response was present in recipients receiving allochimeric molecules, with IgG1 and IgG2a subclasses predominating. Immunohistochemical analysis of allografts demonstrated minimal T cell infiltration and IgG binding to vascular endothelium. CONCLUSION Treatment with allochimeric molecules prevents the development of chronic rejection. Such effect may be in part caused by deviation of host alloantibody responses.