Lower Pretransplant Serum Research Articles

Long-Term Outcomes and Safety Trends of Autologous Stem-Cell Transplantation in Non-Hodgkin Lymphoma: A Report From A Tertiary Care Center in India.

PURPOSEPublished experience with autologous stem-cell transplantation (ASCT) in non-Hodgkin lymphoma (NHL) from the Indian subcontinent is extremely limited. Here, we describe the activity and outcomes of this treatment modality at a large tertiary care center in India.PATIENTS AND METHODSWe retrospectively analyzed adult patients with NHL who were eligible for ASCT and autografted between January 1, 2002, and December 15, 2020, at our transplant unit. Toxicities, complications, and long-term outcomes were compared between patients who underwent transplant during 2002-2012 (group A) and 2013-2020 (group B).RESULTSOverall, 80 patients (group A, n = 37; group B, n = 43) underwent ASCT using peripheral blood stem cells. At a median follow-up of 57.6 months, the 5-year event-free survival (EFS) and overall survival (OS) were 43.5% and 47.6%, respectively, for all patients. More recently (group B), patients had reduced 100-day transplant-related mortality (2.3% v 21.6%, P < .01), improved 3-year EFS (52.9% v 37.3%, P = .04), and superior OS (at 3-year; 63.4% v 43.2%, P = .02). Patients in group B also tolerated the procedure better, with improved resource utilization. In multivariate analysis, an International Prognostic Index (IPI) ≥ 3 at diagnosis adversely affected EFS (hazard ratio [HR] = 2.82, P = .009) and OS (HR = 2.84, P = .01) after ASCT. Low pretransplant serum albumin levels were associated with inferior EFS (HR = 2.68, P = .02) and transplant-related mortality (odds ratio = 10.80, P = .02) after ASCT.CONCLUSIONIt is feasible to achieve comparable short- and long-term outcomes in patients with NHL undergoing ASCT in a resource-poor country with improved supportive care and expertise of the transplant team and center.

Peritransplant Soluble CD30 as a Risk Factor for Slow Kidney Allograft Function, Early Acute Rejection, Worse Long-Term Allograft Function, and Patients' Survival.

Background We aimed to determine whether serum soluble CD30 (sCD30) could identify recipients at high risk for unfavorable early and late kidney transplant outcomes. Methods Serum sCD30 was measured on the day of kidney transplantation and on the 4th day posttransplant. We assessed the value of these measurements in predicting delayed graft function, slow graft function (SGF), acute rejection (AR), pyelonephritis, decline of allograft function after 6 months, and graft and patient survival during 5 years of follow-up in 45 recipients. Results We found the association between low pretransplant serum levels of sCD30 and SGF. The absence of significant decrease of sCD30 on the 4th day posttransplant was characteristic for SGF, early AR (the 8th day–6 months), late AR (>6 months), and early pyelonephritis (the 8th day–2 months). Lower pretransplant and posttransplant sCD30 predicted worse allograft function at 6 months and 2 years, respectively. Higher pretransplant sCD30 was associated with higher frequency of early AR, and worse patients' survival, but only in the recipients of deceased-donor graft. Pretransplant sCD30 also allowed to differentiate patients with early pyelonephritis and early AR. Conclusions Peritransplant sCD30 is useful in identifying patients at risk for unfavorable early and late transplant outcomes.

Incidence and risk factors of hepatocellular carcinoma after orthotopic liver transplantation

The incidence of hepatocellular carcinoma has doubled over the past 2decades, becoming the fifth most common cancer worldwide. Orthotopic liver transplant is the gold standard treatment forthose with hepatocellular carcinoma meeting eligibility criteria, although recurrence rates of hepatocellular carcinoma after orthotopic liver transplant still remain an understudied obstacle. We performed a single-center, retrospective, longitudinal study with the aim of determining the predominant baseline and follow-up variables associated with hepatocellular carcinoma recurrence. We gathered pre- and post-transplant data and conducted univariate and multivariate analysis to assess variables predicting hepatocellular carcinoma recurrence after orthotopic liver transplant. Between 2003 and 2015, 141 patients underwent orthotopic liver transplant for hepatocellular carcinoma. We identified 9 (6.4%) cases of documented hepatocellular carcinoma recurrence. Univariate analysis indicated that the difference in serum alpha-fetoprotein levels (most recent prior to transplant subtracted from maximum level) was lower in the hepatocellular carcinoma recurrence group (median 3ng/mL vs 0ng/mL, P=.052) as well as the pretransplant serum cholesterol level (median 158mg/dL vs 113mg/dL, P=.019) and days between hepatocellular carcinoma neoadjuvant treatment initiation and transplantation (median 122 vs 0, P=.045). Multivariate analysis revealed that a low pretransplant serum cholesterol level (<100mg/dL) was independently associated with hepatocellular carcinoma recurrence (hazard ratio 11.0, P=.004). The risk of hepatocellular carcinoma recurrence after orthotopic liver transplant was low, at 6.4%, in this cohort. Low pretransplant serum cholesterol was the strongest predictor of recurrence and may help clinicians risk stratify patients for appropriate post-transplant monitoring and follow-up.

New-Onset Diabetes After Kidney Transplantation and Pretransplant Hypomagnesemia

Hypomagnesemia is a frequent finding in kidney transplant patients and plays a causal role in insulin resistance and diabetes. The aim of this study was to investigate whether the pretransplant magnesium (Mg) level is a risk factor for the development of new-onset diabetes after kidney transplantation (NODAT) and the presence of relationship between pretransplant hypomagnesemia and the development period of NODAT. Four hundred and nineteen nondiabetic renal transplant recipients were evaluated retrospectively. The patients were divided into NODAT and non-NODAT groups. The time of diagnosis of patients with NODAT was divided into 0 to 3, 3 to 6, 6 to 12 months, and after 12 months. Patients' characteristics and pretransplant Mg levels in NODAT were compared with non-NODAT, and it was investigated whether pretransplant hypomagnesemia was a risk factor for the development of NODAT. Totally 70 (16.6%) patients (36 female [F], mean age 51.7 ± 8.2 years) were diagnosed with NODAT. Three hundred and forty-nine patients (115 F, mean age 43.2 ± 12.5 years) did not have NODAT. Pretransplant mean Mg level was 1.97 ± 0.40 mg/dL in patients with NODAT, while it was 2.5 ± 0.45 mg/dL in non-NODAT patients (P < .001). Serum Mg level was found to be similar in subgroups according to the development period of NODAT (P = .07). When patients were stratified according to quartiles of Mg level, the frequency of NODAT was significantly higher in patients in the lower quartile (Mg < 2.1 mg/dL; P < .001). Older age, high body mass index, and low pretransplant serum Mg levels were established as risk factors for developing NODAT. According to the quartile of Mg level, the risk of developing NODAT was highest in the lowest quartile. Pretransplant hypomagnesemia is an independent risk factor of NODAT. Therefore, it is necessary to closely monitor the Mg levels in the posttransplant period.

Low-serum testosterone levels pre-liver transplantation are associated with reduced rates of early acute allograft rejection in men.

Low pretransplant serum testosterone has recently been associated with increased mortality in men awaiting liver transplantation, but the potential impact on rejection has not yet been investigated. Pretransplantation serum testosterone, SHBG, and other variables were collected on 190 consecutive men who received a liver transplant between 2007 and 2013. Rates of subsequent acute cellular rejection were recorded. Multivariable analysis was performed to define variables associated with rejection and other clinically important end points. Thirty (16%) of 190 men experienced acute cellular rejection. Lower pretransplant testosterone was associated with lower rejection rates, -7% (95% confidence interval [CI], -2% to -12%) per nmol/L decrease in total testosterone and -4% (95% CI, -0.5% to -7%) per 10 pmol/L decrease in free testosterone. Total testosterone (correlation 0.29, P=0.04) and free testosterone (correlation 0.37, P=0.01) correlated significantly with the histological severity of rejection. Older age at transplant (+5% [95% CI, 9%-2%]) per year, and nonautoimmune etiology of liver disease (OR, 1.0 for autoimmune, 0.22 [95% CI, 0.07-0.73] for hepatitis C virus, and 0.58 [95% CI, 0.21-1.71] for other etiologies) were also associated with decreased rejection risk. In a generalized linear model including the covariates testosterone, SHBG, age, etiology, and MELD, total testosterone remained a significant predictor of rejection (adjusted OR, 1.06; P=0.03), as did age at transplant (OR, 0.95; P=0.01). Low preliver transplant serum testosterone independently predicts a decreased risk of acute allograft rejection. Whether testosterone is a marker of disease-associated immune dysfunction or has immune-modulatory effects requires further study.

Pretransplant Serum Hepatitis C Virus RNA Levels Predict Response to Antiviral Treatment after Living Donor Liver Transplantation

BackgroundGiven the limited efficacy and high adverse event rate associated with treatment of recurrent hepatitis C after liver transplantation, an individualized treatment strategy should be considered. The aim of this study was to identify predictors of response to antiviral therapy for hepatitis C after living donor liver transplantation (LDLT) and to study the associated adverse events.MethodsA retrospective chart review was performed on 125 hepatitis C virus (HCV)-positive LDLT recipients who received interferon plus ribavirin and/or peginterferon plus ribavirin therapy at Kyoto University between January 2001 and June 2011.ResultsSerum HCV RNA reached undetectable levels within 48 weeks in 77 (62%) of 125 patients, and these patients were defined as showing virological response (VR). Of 117 patients, 50 (43%) achieved sustained VR (SVR). Predictive factors associated with both VR and SVR by univariate analysis included low pretransplant serum HCV RNA levels, a non-1 HCV genotype, and low pretreatment serum HCV RNA levels. In addition, LDLT from ABO-mismatched donors was significantly associated with VR, and white cell and neutrophil counts before interferon therapy were associated with SVR. Multivariate analysis showed that 2 variables–pretransplant serum HCV RNA level less than 500 kIU/mL and a non-1 HCV genotype–remained in models of both VR and SVR and that an ABO mismatch was associated with VR. No variables with a significant effect on treatment withdrawal were found.ConclusionsVirological response to antiviral therapy in patients with hepatitis C recurring after LDLT can be predicted prior to transplant, based on pretransplant serum HCV-RNA levels and HCV genotype. LDLT from ABO-mismatched donors may contribute to more efficacious interferon therapy.Trial RegistrationUMIN-CTR UMIN000003286

Low serum adiponectin level is predictor of arterial stiffness in new onset diabetes after renal transplantation

Background: The purpose of this study was to determine whether the level of adiponectin in serum of renal transplant patients is associated with arterial stiffness related to new onset diabetes after transplantation (NODAT). Methods: A total of 90 previously non-diabetic patients who underwent renal transplantation between 1999 and 2009 were enrolled. We evaluated their diabetic risk factors, lipid profiles, brachial-ankle pulse wave velocity (baPWV), ankle-brachial blood pressure index (ABPI) and serum adiponectin level before and after transplantation. Results: Eleven (12.2%) patients were diagnosed with NODAT and 79 (87.8%) without (non-NO-DAT). The mean post-transplant serum adiponectin level in NODAT patients was significantly lower than that in non-NODAT patients (11.9 vs. 16.4 μg/ml, p = 0.01), whereas the mean baPWV level in NODAT patients was significantly higher (1686 vs. 1468 cm/s, p = 0.016). We found a significant inverse correlation between mean pre-transplant serum adiponectin and baPWV level (r = -0.27, p = 0.011). Furthermore, patients with lower pretransplant serum adiponectin levels (<20 μg/ml) developed NODAT significantly more frequently than those with higher levels (p = 0.038) and the mean baPWV level in the former was also significantly higher (1520 vs. 1412 cm/s, p = 0.047). Conclusion: Our results indicate that low pre-transplant serum adiponectin level is associated with arterial stiffness in development of NODAT in patients who undergo renal transplantation.

Treat the bones and get less rejection!

Known since antiquity, rickets was a common disease until the beginning of the 20th century. It took many years and the collaborative effort of several laboratories to identify the compound present in cod liver oil responsible for the therapeutic effect against rickets. The vitamin D structure was finally described in 1936 by the German chemist Adolf Windaus (1876–1959). Since then, we have come to understand the synthesis of 1α,25(OH)2-vitamin D3 (calcitriol) and its mechanism of action through a nuclear receptor, VDR, to regulate calcium homeostasis and bone mineralization. VDR is expressed not only in intestinal cells and osteoblasts but also constitutively in monocytes and in activated macrophages, dendritic cells, natural killer cells, T and B cells, which suggests immunomodulatory functions for calcitriol. Calcitriol acts as an inhibitor of the adaptive immune system. It has inhibitory effects on macrophages and dendritic cells. Calcitriol enables dendritic cells with tolerogenic properties (1) and acts directly in Th cells to enhance the development of a Th2 phenotype (2). These features could be of benefit in the transplantation setting. In retrospective studies, the administration of calcitriol to kidney transplant recipients improved graft function, graft survival and decreased episodes of acute rejection (3–5). Similar results have been published for heart transplantation. Low post-operative calcitriol serum concentrations are independently associated with high 1-year mortality in cardiac transplant recipients (6). Patients receiving low-dose calcitriol after cardiac transplantation required substantially lower cumulative doses of cyclosporin for organ rejection without any detectable change in the episodes of rejection (7). What about liver transplantation and calcitriol? We investigated the effect of calcitriol as an immunosuppressive agent in an experimental model for liver transplantation (8). Calcitriol increased the survival of vascularized liver allografts in rats when compared with controls. Vitamin D reduced the concentration of interleukin (IL)-2 and IL-12 in serum and in grafts, and increased IL-4 and IL-10 in the grafts. The rejection activity after transplantation was significantly lower in treated rats compared with vehicle-treated controls. In this issue of Liver International, Bitetto et al. (9) present a highly anticipated clinical study that investigates whether vitamin D has beneficial immune properties after liver transplantation. Based on a collection of 133 liver transplantation recipients, the authors report that a low pretransplant serum 25-OH vitamin D is independently associated with rejection episodes (Banff score ≥6) in the first 2 months following liver transplantation and that the introduction of vitamin D3 supplementation in the first month after liver transplantation is associated with a decreased risk for acute rejection (Banff score ≥3) in the following 3–8 months. These results are not surprising, but are important nonetheless. It is estimated that two-third of patients with cirrhosis and 96% of patients awaiting liver transplantation have low serum vitamin D levels (10) and the present study found optimal vitamin D levels (>30 ng/ml) in only 7.5% of the patients tested. Osteoporosis, which increases the risk of vertebral fractures, occurs in 12–55% of patients with cirrhosis (10). In the months following liver transplantation, further bone loss occurs in most liver recipients and exacerbates pre-existing osteopenia with a high incidence of fracturing (10). Patients listed for a liver transplantation should then receive vitamin D before and after transplantation. This supplementation is safe, well tolerated and appears to have additional non-negligible immune effects. Acute rejection is rarely a serious issue after liver transplantation today. Nevertheless, immunosuppressive drugs have side effects, which limit the long-term benefit of liver transplantation. Calcineurin inhibitors impair renal function and every large liver transplantation centre must provide dialysis for some of their transplant recipients and some even receive kidney transplantation. The hope that mTOR inhibitors could serve as renal protective immunosuppressors is vanishing. A retrospective, controlled study showed that the administration of sirolimus after orthotopic liver transplantation did not protect against renal dysfunction (11). Another case–control retrospective series suggested that the choice of sirolimus for liver transplant patients with chronic renal insufficiency is associated with the stabilization of renal function but conferred no additional benefit over low-dose calcineurin inhibitor regimens and may in fact be disadvantageous in patients with a creatinine clearance of <30 ml/min (12). In this context, vitamin D as a calcineurin inhibitor sparing immunosuppressant in liver transplantation is an attractive option. The retrospective nature of the work of Bitetto is a disadvantage as are the arbitrarily chosen endpoints. It is imperative that prospective randomized studies be designed in the liver transplantation field to establish definitively the immunosuppressive role of vitamin D as it is already the case in the renal transplantation field (13). We should not miss the opportunity to treat the bones and get less rejection!