Puneet Sood

Management and outcome of BK viremia in renal transplant recipients: a prospective single-center study.

Background BK viremia can lead to nephritis, which can progress to irreversible kidney transplant failure. Our prospective study provides management and outcome of BK viremia in renal transplant recipients. Methods Two hundred forty de novo kidney-only recipients were enrolled from July 2007 to July 2010 and followed for 1 year. Standard immunosuppression with Thymoglobulin/interleukin 2 receptor blocker and mycophenolate mofetil/tacrolimus (Tac)/prednisone was employed. Quantitative BK virus (BKV) DNA surveillance in plasma/urine was performed at 1, 3, 6, 12, and 24 months after transplantation. Patients with significant viremia (defined as ≥10,000 viral copies/mL) underwent renal biopsy and treated with 30% to 50% reduction in doses of both mycophenolate mofetil and Tac without antiviral therapy. The target 12-hr Tac trough levels were lowered to 4 to 6 ng/mL in the significant viremia group, whereas the target levels remained unchanged at 5 to 8 ng/mL for all other groups. Results Sixty-five patients (27%) developed BK viremia; 28 (12%) of whom had significant viremia. A total of five (21%) of the 23 (of 28) patients who underwent biopsy presented with subclinical BKV nephritis. The mean plasma BKV DNA declined by 98% (range, 76%–100%) at 1 year after peak viremia. Acute cellular rejection seen in four (14%) of 28 patients, responded to bolus steroids. There was no decline in estimated glomerular filtration rate over time from 1 month after transplantation to 1 year after peak viremia (P=0.57). Conclusion Reduction in immunosuppression alone resulted in the successful resolution of viremia with preservation of renal function and prevention of clinical BKV nephritis and graft loss.

Cell-Free DNA and Active Rejection in Kidney Allografts

Histologic analysis of the allograft biopsy specimen is the standard method used to differentiate rejection from other injury in kidney transplants. Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive test of allograft injury that may enable more frequent, quantitative, and safer assessment of allograft rejection and injury status. To investigate this possibility, we prospectively collected blood specimens at scheduled intervals and at the time of clinically indicated biopsies. In 102 kidney recipients, we measured plasma levels of dd-cfDNA and correlated the levels with allograft rejection status ascertained by histology in 107 biopsy specimens. The dd-cfDNA level discriminated between biopsy specimens showing any rejection (T cell-mediated rejection or antibody-mediated rejection [ABMR]) and controls (no rejection histologically), P<0.001 (receiver operating characteristic area under the curve [AUC], 0.74; 95% confidence interval [95% CI], 0.61 to 0.86). Positive and negative predictive values for active rejection at a cutoff of 1.0% dd-cfDNA were 61% and 84%, respectively. The AUC for discriminating ABMR from samples without ABMR was 0.87 (95% CI, 0.75 to 0.97). Positive and negative predictive values for ABMR at a cutoff of 1.0% dd-cfDNA were 44% and 96%, respectively. Median dd-cfDNA was 2.9% (ABMR), 1.2% (T cell-mediated types ≥IB), 0.2% (T cell-mediated type IA), and 0.3% in controls (P=0.05 for T cell-mediated rejection types ≥IB versus controls). Thus, dd-cfDNA may be used to assess allograft rejection and injury; dd-cfDNA levels <1% reflect the absence of active rejection (T cell-mediated type ≥IB or ABMR) and levels >1% indicate a probability of active rejection.

Donor and recipient BKV-specific IgG antibody and posttransplantation BKV infection: a prospective single-center study.

Background The study evaluated the relationship of pretransplantation BK virus (BKV)–specific donor and recipient serostatus to posttransplantation BKV infection. Methods Two hundred forty adult de novo kidney-only recipients and 15 pediatric recipients were prospectively enrolled and followed for a minimum of 18 months. Pretransplantation BKV serostatus was available for 192 adult and 11 pediatric donor–recipient pairs. Based on BKV-specific IgG enzyme immunoassay ≥8 units, subjects were divided into four groups: D+R+, D+R-, D-R+, and D-R-. BKV DNA surveillance was performed at 1, 3, 6, 12, and 24 months. The outcomes studied were development of any BKV infection, viremia, and significant viremia (≥10,000 copies/mL plasma). Results Of the 192 adult subjects (D+R- [n=41], D+R+ [n=42], D-R+ [n=41], and D-R- [n=68]), 89 of 192 developed any BKV infection and 62 of 89 developed BK insignificant viremia (n=33) and significant viremia (n=29). Any BKV infection developed in 25 of 41, 22 of 42, 17 of 41, and 25 of 68 in the D+R-, D+R+, D-R+, and D-R- groups, respectively. Any viremia (20 of 41) and significant viremia (10 of 41) seen in the D+R- group was significantly higher than other groups (P=0.014). In 11 pediatric recipients, infection was seen only in the D+R- group. Overall, infection was highest in the D+R- group and lowest in the D-R- group. Conclusions BKV serostatus can be used to risk stratify patients for posttransplantation infection.

Commercially Available Immunoglobulins Contain Virus Neutralizing Antibodies Against All Major Genotypes of Polyomavirus BK

Neutralizing antibodies (NAbs) form the basis of immunotherapeutic strategies against many important human viral infections. Accordingly, we studied the prevalence, titer, genotype‐specificity, and mechanism of action of anti‐polyomavirus BK (BKV) NAbs in commercially available human immune globulin (IG) preparations designed for intravenous (IV) use. Pseudovirions (PsV) of genotypes Ia, Ib2, Ic, II, III, and IV were generated by co‐transfecting a reporter plasmid encoding luciferase and expression plasmids containing synthetic codon‐modified VP1, VP2, and VP3 capsid protein genes into 293TT cells. NAbs were measured using luminometry. All IG preparations neutralized all BKV genotypes, with mean EC50 titers as high as 254 899 for genotype Ia and 6,666 for genotype IV. Neutralizing titers against genotypes II and III were higher than expected, adding to growing evidence that infections with these genotypes are more common than currently appreciated. Batch to batch variation in different lots of IG was within the limits of experimental error. Antibody mediated virus neutralizing was dose dependent, modestly enhanced by complement, genotype‐specific, and achieved without effect on viral aggregation, capsid morphology, elution, or host cell release. IG contains potent NAbs capable of neutralizing all major BKV genotypes. Clinical trials based on sound pharmacokinetic principles are needed to explore prophylactic and therapeutic applications of these anti‐viral effects, until effective small molecule inhibitors of BKV replication can be developed.

Kidney allograft surveillance biopsy practices across US transplant centers: A UNOS survey

The approach to the diagnosis and management of subclinical rejection (SCR) in kidney transplant recipients remains controversial.

Subclinical Rejection in Renal Transplantation: Reappraised

Abstract Short-term outcomes in renal transplantation have improved significantly in the past few years. However, the improvement in long-term outcomes has been modest. The reasons for graft failure beyond the first year of transplantation have been attributed to several different factors. We believe that subclinical rejection (SCR) may be 1 of the factors that contribute to graft loss in the long run. We also believe that there are data to suggest that SCR leads to progressive fibrosis and loss of graft function. This has been demonstrated even in patients who have mild degrees of subclinical inflammation. This review outlines the major studies that have been published on this important topic. It also outlines potential risk factors for the development of SCR. The current approach and diagnostic methods are discussed as well as their pros and cons. Newer noninvasive methods of diagnosis as well as molecular diagnostics and their merits and shortcomings are also discussed in some depth. Thus, the proposed state of the art review on SCR will create a renewed interest at all levels including transplant clinicians, transplant researchers, pharmaceutical industries as well as regulatory organizations.

Lower prevalence of BK virus infection in African American renal transplant recipients: a prospective study.

Background. Because the occurrence of BK virus (BKV) nephritis is far less frequent than BK viremia or viruria, analysis of risk factors for BKV nephritis as an endpoint could lead to erroneous findings. We undertook a prospective study to evaluate the risk factors for the occurrence of BKV infections using BK viruria and viremia as endpoints. Methods. Two hundred forty renal only transplant recipients were prospectively enrolled into our institutional review board-approved single center study to evaluate various aspects of posttransplant BKV infection. All patients were followed up for a minimum of 6 months posttransplant. Results. Of the 240 subjects, 154 were whites, 61 African Americans, and 25 belonged to other races. A total of 94 developed BKV infection (any degree of BK viruria or viremia) whereas 146 developed no infection. Among these, 33 had BK viruria alone, 61 had BK viremia with viruria and 25 had significant viremia defined as BKV DNA more than 10,000 copies/mL of plasma. Lower proportion of African Americans developed BKV infection, 14 of 61 (23%), as opposed to whites, 67 of 154 (47%). Logistic regression model showed lower risk of any BKV infection in African American recipient race (OR, 0.38; 95% CI, 0.17–0.82; P=0.016) and higher risk of significant BKV infection with occurrence of acute rejection (OR, 3.9; 95% CI, 1.31–11.8; P=0.015). The Kaplan-Meier analysis shows a trend toward greater freedom from BKV infection in African Americans as opposed to other racial groups (P=0.33). Conclusion. Renal transplant recipients of African American race had a lower risk of posttransplant BKV infection compared with whites, independent of other confounding risk factors.

Transplantation: Rituximab induction for prevention of HLA-antibody rebound

Desensitization therapy enables HLA-incompatible transplantation. However, desensitized patients have an increased risk of antibody-mediated rejection, and the presence of donor-specific antibodies (DSAs) is associated with poor outcomes. A new study has assessed the effect of rituximab induction on DSA production in kidney transplant recipients with high immunological risk.

Outcomes of Patients Receiving Maintenance Dialysis Admitted Over Weekends

BACKGROUND Hospital admissions over weekends have been associated with worse outcomes in different patient populations. The cause of this difference in outcomes remains unclear; however, different staffing patterns over weekends have been speculated to contribute. We evaluated outcomes in patients on maintenance dialysis therapy admitted over weekends using a national database. STUDY DESIGN Retrospective cohort study. SETTING & PARTICIPANTS We included nonelective admissions of adult patients (≥18 years) on maintenance dialysis therapy (n = 3,278,572) identified using appropriate International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for 2005-2009 using the Nationwide Inpatient Sample database. PREDICTOR Weekend versus weekday admission. OUTCOMES The primary outcome measure was all-cause in-hospital mortality. Secondary outcomes included mortality by day 3 of admission, length of hospital stay, time to death, and discharge disposition. MEASUREMENTS We adjusted for patient and hospital characteristics, payer, year, comorbid conditions, and primary discharge diagnosis common to maintenance dialysis patients. RESULTS There were an estimated 704,491 admissions over weekends versus 2,574,081 over weekdays. Unadjusted all-cause in-hospital mortality was 40,666 (5.8%) for weekend admissions in comparison to 138,517 (5.4%) for weekday admissions (P < 0.001). In a multivariable model, patients admitted over weekends had higher all-cause in-hospital mortality (OR, 1.06; 95% CI, 1.01-1.10) in comparison to those admitted over weekdays and higher mortality during the first 3 days of admission (OR, 1.18; 95% CI, 1.10-1.26). Patients admitted over weekends were less likely to be discharged to home, had longer hospital stays, and had shorter times to death compared with those admitted over weekdays on adjusted analysis. LIMITATIONS Use of ICD-9-CM codes to identify patients, defining weekend as midnight Friday to midnight Sunday. CONCLUSIONS Maintenance dialysis patients admitted over weekends have increased mortality rates and longer lengths of stay compared with those admitted over weekdays. Further studies are needed to identify the reasons for worse outcomes for weekend admissions in this patient population.

Low vitamin D exposure is associated with higher risk of infection in renal transplant recipients

Vitamin D is a steroid hormone with multiple vital roles within the immune system. Various studies evaluated the influence of vitamin D on infections postrenal transplantation and found contrasting results. This study aimed to assess the relationship between vitamin D status and the incidence of infection in renal transplant recipients.