Vikas R. Dharnidharka

Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression.

Background. Posttransplant lymphoproliferative disorders (PTLD) still represent a major preoccupation after renal transplantation, even in the most recent years. Methods. We analyzed the incidence, risk, and prognostic factors of PTLD in a cohort of kidney recipients using the United States Renal Data System. Results. Among 25,127 Medicare patients transplanted between 1996 and 2000, 344 developed a PTLD defined as a non-Hodgkin lymphoma (1.4%). History of pretransplant malignancy (adjusted hazard ratio [AHR]=3.54, CI 2.31–5.43), younger age (AHR=1.91, CI 1.18–3.1), fewer HLA matches (AHR=1.32, CI 1.1–1.59) and treatment by ATG (AHR=1.55, CI 1.2–1.99) and OKT3 (AHR=1.37, CI 1–1.76), especially if given for rejection therapy were associated with an increased risk of PTLD. Mycophenolate and azathioprine were associated with a lower risk of PTLD (AHR=0.6, CI 0.47–0.78 and AHR=0.66, CI 0.46–0.95, respectively). IL2-receptor inhibitors and sirolimus did not modify the risk of PTLD. Patients without induction therapy treated with tacrolimus were at greater risk of lymphoma than those treated with new formulations of cyclosporine and those treated with antimetabolites (mycophenolate and azathioprine) have a lower risk of PTLD than those without. Patients with PTLD had poor survival (64% vs. 80% at 5 years). Older age, pretransplant malignancy and OKT3 were risk factors for death whereas treatment with mycophenolate was associated with a better survival (AHR=0.49, CI=0.28–0.82). Conclusions. Our study highlights the contribution of patient history and immunosuppression in the risk of PTLD in the era of modern immunosuppression.

Outcomes from pandemic influenza A H1N1 infection in recipients of solid-organ transplants: a multicentre cohort study

BACKGROUND There are few data on the epidemiology and outcomes of influenza infection in recipients of solid-organ transplants. We aimed to establish the outcomes of pandemic influenza A H1N1 and factors leading to severe disease in a cohort of patients who had received transplants. METHODS We did a multicentre cohort study of adults and children who had received organ transplants with microbiological confirmation of influenza A infection from April to December, 2009. Centres were identified through the American Society of Transplantation Influenza Collaborative Study Group. Demographics, clinical presentation, treatment, and outcomes were assessed. Severity of disease was measured by admission to hospital and intensive care units (ICUs). The data were analysed with descriptive statistics. Proportions were compared by use of chi(2) tests. We used univariate analysis to identify factors leading to pneumonia, admission to hospital, and admission to an ICU. Multivariate analysis was done by use of a stepwise logistic regression model. We analysed deaths with Kaplan-Meier survival analysis. FINDINGS We assessed 237 cases of medically attended influenza A H1N1 reported from 26 transplant centres during the study period. Transplant types included kidney, liver, heart, lung, and others. Both adults (154 patients; median age 47 years) and children (83; 9 years) were assessed. Median time from transplant was 3.6 years. 167 (71%) of 237 patients were admitted to hospital. Data on complications were available for 230 patients; 73 (32%) had pneumonia, 37 (16%) were admitted to ICUs, and ten (4%) died. Antiviral treatment was used in 223 (94%) patients (primarily oseltamivir monotherapy). Seven (8%) patients given antiviral drugs within 48 h of symptom onset were admitted to an ICU compared with 28 (22.4%) given antivirals later (p=0.007). Children who received transplants were less likely to present with pneumonia than adults, but rates of admission to hospital and ICU were similar. INTERPRETATION Influenza A H1N1 caused substantial morbidity in recipients of solid-organ transplants during the 2009-10 pandemic. Starting antiviral therapy early is associated with clinical benefit as measured by need for ICU admission and mechanical ventilation. FUNDING None.

Improved equations estimating GFR in children with chronic kidney disease using an immunonephelometric determination of cystatin C.

The Chronic Kidney Disease in Children study is a cohort of about 600 children with chronic kidney disease (CKD) in the United States and Canada. The independent variable for our observations was a measurement of glomerular filtration rate (GFR) by iohexol disappearance (iGFR) at the first two visits one year apart and during alternate years thereafter. In a previous report, we had developed GFR estimating equations utilizing serum creatinine, blood urea nitrogen, height, gender and cystatin C measured by an immunoturbidimetric method; however the correlation coefficient of cystatin C and GFR (-0.69) was less robust than expected. Therefore, 495 samples were re-assayed using immunonephelometry. The reciprocal of immunonephelometric cystatin C was as well correlated with iGFR as was height/serum creatinine (both 0.88). We developed a new GFR estimating equation using a random 2/3 of 965 person-visits and applied it to the remaining 1/3 as a validation data set. In the validation data set, the correlation of the estimated GFR with iGFR was 0.92 with high precision and no bias; 91% and 45% of eGFR values were within 30% and 10% of iGFR, respectively. This equation works well in children with CKD in a range of GFR from 15 to 75 ml/min per 1.73 m2. Further studies are needed to establish the applicability to children of normal stature and muscle mass, and higher GFR.

Risk factors for posttransplant lymphoproliferative disorder (PTLD) in pediatric kidney transplantation: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).

Background. Posttransplant lymphoproliferative disorder (PTLD) is an important complication of transplantation. The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database has documented 56 cases of PTLD, the largest such series to date. Methods. We analyzed the available longitudinal and multicenter data in the NAPRTCS database to evaluate the demographic and therapeutic risk factors and the temporal trends for PTLD in children after renal transplantation. Results. The overall incidence of PTLD was 1.2% of all patients or 298/100,000 posttransplantation years of follow-up. However, this incidence increased from 254/100,000 years between 1987 and 1991 to 395/100,000 years from 1992 onwards. In the same periods, the time to PTLD decreased from a median of 356 days (range 64–3048) to a median of 190 days (range 42–944). PTLD occurred with greater frequency in white children (P =0.003) and in cadaver donor transplants (P =0.019), but there was no significant predilection for gender, younger children (0–5 years), or primary diagnosis. No significant difference was found in the use of anti–T-cell antibodies or in doses of CsA, azathioprine, or prednisone at 1 month, 6 months, and 1 year. Between 1996 and 1997, 69 patients were initiated with tacrolimus. Eight cases of PTLD were identified in these recipients to date (prevalence rate 11.5%), compared with 46/4084 (1.1%) where cyclosporine was used (P <0.0001). Conclusions. There is a trend towards increasing incidence and earlier occurrence of PTLD in the pediatric renal transplant population. White race and cadaver donor sources are risk factors not reported before. Continued monitoring of tacrolimus immunosuppression is important.

Post‐Transplant Lymphoproliferative Disorder in the United States: Young Caucasian Males are at Highest Risk

We have previously documented Caucasian race and cadaver donor source as risk factors for post‐transplant lymphoproliferative disorder (PTLD) development in recipients registered in the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). We analyzed data from the Scientific Registry of the United Network of Organ Sharing (UNOS) (from January 1988 to December 1999) to determine risk factors for the development of PTLD in all organ systems and its frequency, and we compared these factors to the risk factors in the most recent NAPRTCS database (1987–2000). In the UNOS database, PTLD was reported in 2365 of 205 114 organ‐transplant recipients (1.2%). PTLD was reported in 3% or more of all intestinal and thoracic organ recipients, but in less than 1% of other abdominal organ recipients. Recipient age < 18 years, Caucasian race and male gender were independent risk factors [Odds Ratios (OR) 2.81, 2.22 and 1.40, respectively, p = 0.0001], but not cadaver donor source. The combination of all three risk factors increased the OR to 8.78. The occurrence of PTLD showed a significant rise per year for heart‐lung, kidney, kidney‐pancreas and liver transplants, but decreased significantly for heart transplants (p < 0.001). Similar frequencies of PTLD were found in smaller organ‐specific registries of heart, intestine, pediatric liver and pediatric kidney transplants. The PTLD incidence per year and incidence density have increased in recent years. Young Caucasian males are at highest risk for PTLD development among solid‐organ‐transplant recipients. The incidence of PTLD is increasing.

Dissociation of depletional induction and posttransplant lymphoproliferative disease in kidney recipients treated with alemtuzumab.

Transplant patients are at the risk for posttransplant lymphoproliferative disease (PTLD), a virally‐driven malignancy. Induction with the depleting antibody preparations Thymoglobulin and OKT3 is associated with PTLD suggesting that the T‐cell depletion increases PTLD risk. We therefore studied 59 560 kidney recipients from the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) database for a relationship between induction agent use and PTLD. Two agents with comparable T‐cell depletional effects, alemtuzumab and Thymoglobulin, were compared to nondepletional induction agents or no induction. The overall incidence of PTLD was 0.46% and differed significantly by induction strategy (p < 0.01): without induction (0.43%), basiliximab (0.38%), daclizumab (0.33%), Thymoglobulin (0.67%) and alemtuzumab (0.37%). Thymoglobulin was associated with significantly increased PTLD risk (p = 0.0025), but alemtuzumab (p = 0.74), basiliximab (p = 0.33) and daclizumab, which trended toward a protective effect (p = 0.06), were not. Alemtuzumab and Thymoglobulin treated patients did not differ in any established parameter affecting PTLD risk although alemtuzumab is known to have a more pronounced B‐cell depleting effect. Interestingly, maintenance therapy with an mTOR inhibitor was strongly associated with PTLD (0.71%, p < 0.0001). Thus, depletional induction is not an independent risk factor for PTLD. Rather, maintenance drug selection or perhaps the balance between B‐ and T‐cell depletion may be more relevant determinants of PTLD risk.

Post‐Transplant Infections Now Exceed Acute Rejection as Cause for Hospitalization: A Report of the NAPRTCS

Newer immunosuppressive agents have dramatically reduced the rates of acute graft rejection (AR) over the last decade but may have exacerbated the problem of post‐transplant infections (PTI). We analyzed data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) to determine the risks of hospitalization from PTI vs. AR in the years 1987–2000. For patients transplanted in 1987, the AR‐associated hospitalization rate exceeded the equivalent hospitalization rate for PTI at both early (1–6 months) and later time points (6–24 months). In contrast, for patients transplanted in the year 2000, the PTI‐associated hospitalization rate was twice that for AR‐associated hospitalization during each time period. During the first two years post‐transplant, rates of AR hospitalization trended significantly downwards (p < 0.001) while rates of PTI‐associated hospitalization stayed constant. In the 6–24‐month time period post‐transplant, the risk of bacterial and viral infection‐related hospitalization rose significantly from 1987 to 2000 (p < 0.001 for trend by transplant year). We conclude that the causes of hospitalization at all times up to 24 months post‐transplant, including the critical early 6 months, have shifted away from AR to PTI.

Adolescent Transition to Adult Care in Solid Organ Transplantation: A consensus conference report

Transition of care from pediatric to adult‐oriented health care providers is difficult for children with special health care needs. Children who have received solid organ transplants and their providers experience the same difficulties and frustrations as children with other major illnesses. A consensus conference was organized by several transplant organizations to identify major issues in this area and recommend possible approaches to easing the process of transition for solid organ transplant recipients. This report summarizes the discussions and recommendations.

An Optn Analysis of National Registry Data on Treatment of Bk Virus Allograft Nephropathy in the United States

Introduction. Published data for BK virus allograft nephropathy, a recently emerged graft-threatening complication of kidney transplantation, are from limited-center series. Since June 30, 2004, the Organ Procurement Transplant Network national registry in the United States started collecting data on treatment of BK virus (TBKV) on the kidney follow-up forms. This study determined the rates of TBKV within 24 months posttransplant time and elucidated the risk factors for TBKV from this multicenter database. Methods. We queried the database for all primary and solitary kidney transplant recipients transplanted between January 1, 2003 and December 31, 2006, followed through July 18, 2008, and who were reported to have TBKV. Cumulative incidence of TBKV over time was estimated using Kaplan-Meier (K-M) method to reduce potential under reporting. A Cox proportional hazards regression model was fitted to determine risk factors for TBKV development, and time dependent Cox model was fitted to determine if TBKV was associated with higher risk of graft loss. Results. We included 48,292 primary and solitary kidney transplants from the US Organ Procurement Transplant Network database. The cumulative K-M incidence of BKVAN kept rising over time (0.70% at 6 months posttransplant to 2.18% at 1 year, 3.45% at 2 years and 6.6% at 5 years). Risk for BKVAN was higher with certain immunosuppressive regimens that included rabbit antithymocyte globulin or tacrolimus/mycophenolate combinations. Higher center volume and living kidney donation exerted a protective effect. Of concern, TBKV rates were significantly higher in more recent transplant years. TBKV report was associated with higher risk of subsequent graft loss (adjusted hazard ratio=1.69, P<0.001).

Progressive Multifocal Leukoencephalopathy and Use of Mycophenolate Mofetil After Kidney Transplantation

Mycophenolate mofetil (MMF) use may be associated with progressive multifocal leukoencephalopathy (PML). We conducted a retrospective cohort study of 32,757 renal transplant recipients using the United States Renal Data System kidney transplant files for the incidence, prognosis, and clinical features associated with PML occurring after kidney transplant. Subjects were transplanted from January 1, 2000 to July 31, 2004 and followed through December 31, 2004. The incidence density of PML in MMF users was 14.4 cases/100,000 person-years at risk versus 0 for non-MMF users (P=0.11) by log rank test. Factors significantly associated with PML were BK virus infection (22.2% vs. 1.1%), pretransplant transfusion (75% vs. 34%), panel reactive antibody more than 20% (56% vs. 14%), and use of antirejection medications in the first year (33% vs. 9.2%), all P less than 0.05. PML is rare in the renal transplant population. There was no significant association between PML and MMF, but MMF use in this cohort is too high to accurately assess an association.