Jürg Steiger

Reducing Immunosuppression Preserves Allograft Function in Presumptive and Definitive Polyomavirus‐Associated Nephropathy

Early detection of polyomavirus BK (BKV) viremia and reduction of immunosuppression is recommended for preventing polyomavirus‐associated nephropathy (PyVAN), but systematic histological evaluations were not performed in previous studies. We routinely screen for decoy cells and, if positive, measure plasma BKV‐loads. In a cohort of 203 consecutive renal transplantations performed from 2005–2008, 38 patients (19%) developed BKV‐viremia and were treated with reduction of immunosuppression. Based on subsequent allograft biopsy results and peak BKV‐viremia, patients were assigned to three groups: (i) definitive PyVAN (n = 13), (ii) presumptive PyVAN defined by plasma BKV‐loads of ≥4 log10 copies/ml (n = 17) and (iii) low BKV‐viremia (n = 8). Clearance of BKV‐viremia was achieved in 35/38 patients (92%) and subsequent clinical rejection occurred in 3/35 patients (8.6%), both without any difference among the groups. Patients with definitive PyVAN had higher peak plasma BKV‐loads and required longer time for clearance (8.8 vs. 4.6 vs. 2.9 months; p = 0.001). However, allograft function remained stable from baseline to last follow‐up at 34 months (range 18–60) in all three groups with median serum creatinine of 1.6 mg/dl, 1.6 mg/dl and 1.3 mg/dl, respectively. We conclude that screening for BKV‐replication and reduction of immunosuppression is an effective strategy to preserve medium‐term allograft function even in patients developing definitive PyVAN.

Polyomavirus BK-Specific Cellular Immune Response to VP1 and Large T-Antigen in Kidney Transplant Recipients

Polyomavirus BK (BKV) is the primary cause of polyomavirus‐associated nephropathy (PVAN) in kidney transplant (KT) recipients. Using ELISpot assays, we compared the frequency of interferon‐γ (IFN‐γ) secreting peripheral blood mononuclear cells (PBMC) after stimulation with overlapping peptide pools covering BKV large T‐antigen (LT) and VP1 capsid proteins (VP1). In 10 healthy donors, LT and VP1 responses were low with median 24 (range 15–95) and 25 (7–113) spot‐forming units/106 PBMC (SFU), respectively. In 42 KT patients with current or recent plasma BKV loads, median LT and VP1 responses of 29 (0–524) and 114 (0–1432) SFU were detected, respectively. In KT patients with decreasing or past plasma BKV loads, significantly higher median BKV‐specific IFN‐γ responses were detected compared to KT patients with increasing or persisting BKV loads [LT: 78 (8–524) vs. 22 (0–120) SFU, p = 0.003; VP1: 285 (45–1432) vs. 53 (0–423) SFU, p = 0.001, respectively]. VP1‐specific IFN‐γ responses were higher and more likely to involve CD4+ T cells, while CD8+ T cells were more frequently directed against LT. Stimulation with JCV‐specific VP1 and LT peptides indicated only low‐level cross‐recognition. The data suggest that control of BKV replication is correlated with differentiated expansion of BKV‐specific cellular immune responses.

Prevalence and Risk Factors of Non‐Adherence with Immunosuppressive Medication in Kidney Transplant Patients

Non‐adherence with immunosuppressive regimen is a major risk factor for poor outcome after kidney transplantation. Identifying patients at risk for non‐adherence requires understanding the risk factors for non‐adherence. This prospective study included a convenience sample of 249 adult kidney transplant patients >1 year post‐transplant. Non‐adherence was monitored electronically using MEMS®. Selected socio‐economic, therapy‐, patient‐, condition‐ and healthcare team‐related risk factors for non‐adherence were assessed. Period prevalences were expressed as the percent of prescribed doses taken (taking adherence), the percent of correctly dosed days (dosing adherence), the percentage of inter‐dose intervals not exceeding 25% of the prescribed interval (timing adherence), and the number of drug holidays per 100 days (no intake for > 48 h if once daily or for > 24 h if twice daily intake). Testing occurred by simple mixed logistic regression analysis. Factors significant after correction for multiple testing were entered into a multiple logistic regression model. Mean taking, dosing, timing adherence, and drug holidays were 98%, 96%, 93%, and 1.1 days, respectively. Non‐adherence was associated with lower self‐efficacy, higher self‐reported non‐adherence, no pillbox usage, and male gender. Adherence declined between Monday and Sunday. This study provides a framework for identifying patients at risk for non‐adherence and for developing adherence‐enhancing interventions.

Supporting medication adherence in renal transplantation (SMART): a pilot RCT to improve adherence to immunosuppressive regimens

Abstract:  Background:  Although non‐adherence to an immunosuppressive regimen (NAH) is a major risk factor for poor outcome after renal transplantation (RTx), very few studies have examined non‐adherence intervention in this context. This pilot randomized controlled trial (RCT) tested the efficacy of an educational–behavioural intervention to increase adherence in non‐adherent RTx patients. We also assessed how NAH evolves over time.

Rapid Dynamics of Polyomavirus Type BK in Renal Transplant Recipients

BACKGROUND Polyomavirus type BK-associated nephropathy (PVAN) is an emerging cause of early renal transplant failure. No specific antiviral treatment has been established. Current interventions rely on improving immune functions by reducing immunosuppression. In patients with PVAN, a high BK virus (BKV) load is detectable in plasma. However, the relationship between BKV replication and disease is not well understood. METHODS In a retrospective analysis of BKV plasma load in renal transplant recipients undergoing allograft nephrectomy (n = 3) or changes in immunosuppressive regimen (n = 12), we calculated viral clearance rates and generation times and estimated the loss of BKV-infected renal cells. RESULTS After nephrectomy, BKV clearance was fast (viral half-life [t(1/2)], 1-2 h) or moderately fast (t(1/2), 20-38 h), depending on the sampling density, but it was independent of continued immunosuppressive regimens. After changing immunosuppressive regimens, BKV was cleared with a t(1/2) of 6 h-17 days. Using the basic reproductive ratio, the efficacies of intervention ranged from 7% to 83% (mean, 28%; median, 22%). CONCLUSION The results emphasize that high-level BKV replication is a major pathogenetic factor that may have implications for genome rearrangements, immune evasion, and antiviral resistance.

Examining assumptions regarding valid electronic monitoring of medication therapy: development of a validation framework and its application on a European sample of kidney transplant patients

BackgroundElectronic monitoring (EM) is used increasingly to measure medication non-adherence. Unbiased EM assessment requires fulfillment of assumptions. The purpose of this study was to determine assumptions needed for internal and external validity of EM measurement. To test internal validity, we examined if (1) EM equipment functioned correctly, (2) if all EM bottle openings corresponded to actual drug intake, and (3) if EM did not influence a patients normal adherence behavior. To assess external validity, we examined if there were indications that using EM affected the sample representativeness.MethodsWe used data from the Supporting Medication Adherence in Renal Transplantation (SMART) study, which included 250 adult renal transplant patients whose adherence to immunosuppressive drugs was measured during 3 months with the Medication Event Monitoring System (MEMS). Internal validity was determined by assessing the prevalence of nonfunctioning EM systems, the prevalence of patient-reported discrepancies between cap openings and actual intakes (using contemporaneous notes and interview at the end of the study), and by exploring whether adherence was initially uncharacteristically high and decreased over time (an indication of a possible EM intervention effect). Sample representativeness was examined by screening for differences between participants and non-participants or drop outs on non-adherence.ResultsOur analysis revealed that some assumptions were not fulfilled: 1) one cap malfunctioned (0.4%), 2) self-reported mismatches between bottle openings and actual drug intake occurred in 62% of the patients (n = 155), and 3) adherence decreased over the first 5 weeks of the monitoring, indicating that EM had a waning intervention effect.ConclusionThe validity assumptions presented in this article should be checked in future studies using EM as a measure of medication non-adherence.

Acute Renal Failure on Immune Reconstitution in an HIV-Positive Patient with Miliary Tuberculosis

Immune reconstitution syndrome following HAART in human immunodeficiency virus (HIV)-infected patients is characterized by inflammatory worsening of organ functions despite improvement in HIV surrogate markers of HIV infection. We describe a patient with miliary tuberculosis and urinary shedding of acid fast bacilli who developed acute renal failure 8 weeks after initiation of antituberculosis therapy and 6 weeks after initiation of HAART. The diagnostic workup and further course of disease implicated immune reconstitution syndrome as the cause of acute renal failure.

IL1B and DEFB1 Polymorphisms Increase Susceptibility to Invasive Mold Infection After Solid Organ Transplantation

BACKGROUND Single-nucleotide polymorphisms (SNPs) in immune genes have been associated with susceptibility to invasive mold infection (IMI) among hematopoietic stem cell but not solid-organ transplant (SOT) recipients. METHODS Twenty-four SNPs from systematically selected genes were genotyped among 1101 SOT recipients (715 kidney transplant recipients, 190 liver transplant recipients, 102 lung transplant recipients, 79 heart transplant recipients, and 15 recipients of other transplants) from the Swiss Transplant Cohort Study. Association between SNPs and the end point were assessed by log-rank test and Cox regression models. Cytokine production upon Aspergillus stimulation was measured by enzyme-linked immunosorbent assay in peripheral blood mononuclear cells (PBMCs) from healthy volunteers and correlated with relevant genotypes. RESULTS Mold colonization (n = 45) and proven/probable IMI (n = 26) were associated with polymorphisms in the genes encoding interleukin 1β (IL1B; rs16944; recessive mode, P = .001 for colonization and P = .00005 for IMI, by the log-rank test), interleukin 1 receptor antagonist (IL1RN; rs419598; P = .01 and P = .02, respectively), and β-defensin 1 (DEFB1; rs1800972; P = .001 and P = .0002, respectively). The associations with IL1B and DEFB1 remained significant in a multivariate regression model (P = .002 for IL1B rs16944; P = .01 for DEFB1 rs1800972). The presence of 2 copies of the rare allele of rs16944 or rs419598 was associated with reduced Aspergillus-induced interleukin 1β and tumor necrosis factor α secretion by PBMCs. CONCLUSIONS Functional polymorphisms in IL1B and DEFB1 influence susceptibility to mold infection in SOT recipients. This observation may contribute to individual risk stratification.

Prevalence, severity and correlates of alcohol use in adult renal transplant recipients

Abstract: Background: Severe alcohol use is recognized as a major public health concern, even though light to moderate alcohol use might have beneficial effects on health. Alcohol use has been studied to some extent in solid organ transplant populations, yet evidence is lacking on alcohol use and its correlates in the renal transplant population. The aim of this study was therefore to determine the prevalence, severity and correlates of alcohol use in renal transplant recipients.

Polymorphisms in the lectin pathway of complement activation influence the incidence of acute rejection and graft outcome after kidney transplantation

There are conflicting data on the role of the lectin pathway of complement activation and its recognition molecules in acute rejection and outcome after transplantation. To help resolve this we analyzed polymorphisms and serum levels of lectin pathway components in 710 consecutive kidney transplant recipients enrolled in the nationwide Swiss Transplant Cohort Study, together with all biopsy-proven rejection episodes and 1-year graft and patient survival. Functional mannose-binding lectin (MBL) levels were determined in serum samples, and previously described MBL2, ficolin 2, and MBL-associated serine protease 2 polymorphisms were genotyped. Low MBL serum levels and deficient MBL2 diplotypes were associated with a higher incidence of acute cellular rejection during the first year, in particular in recipients of deceased-donor kidneys. This association remained significant (hazard ratio 1.75, 95% confidence interval 1.18-2.60) in a Cox regression model after adjustment for relevant covariates. In contrast, there was no significant association with rates of antibody-mediated rejection, patient death, early graft dysfunction or loss. Thus, results in a prospective multicenter contemporary cohort suggest that MBL2 polymorphisms result in low MBL serum levels and are associated with acute cellular rejection after kidney transplantation. Since MBL deficiency is a relatively frequent trait in the normal population, our findings may lead to individual risk stratification and customized immunosuppression.