Current evidence on vitamin D deficiency and kidney transplant: What's new?

Kidney transplant is the treatment of choice for end-stage chronic kidney disease. Kidneys generate 1,25-dihydroxyvitamin D (calcitriol) from 25-hydroxyvitamin D (calcidiol) for circulation in the blood to regulate calcium levels. Transplant patients with low calcidiol levels have an increased risk of metabolic and endocrine problems, cardiovascular disease, type 2 diabetes mellitus, poor graft survival, bone disorders, cancer, and mortality rate. The recommended calcidiol level after transplant is at least 30 ng/mL (75 nmol/L), which could require 1000-3000 IU/d vitamin D3 to achieve. Vitamin D3 supplementation studies have found improved endothelial function and acute rejection episodes. However, since kidney function may still be impaired, raising calcidiol levels may not lead to normal calcitriol levels. Thus, supplementation with calcitriol or an analog, alfacalcidiol, is often employed. Some beneficial effects found include possible improved bone health and reduced risk of chronic allograft nephropathy and cancer.

Novel insights in the clinical management of hyperimmune patients before and after transplantation.

Despite improvements in anti-Human Leucocyte Antigens antibody detection, identification, and characterization offer a better in peri-operative management techniques, antibodies remain a serious cause of morbidity and mortality for patients both before and after organ transplantation. Hyperimmune patients are disadvantaged by having to wait longer to receive an organ from a suitably matched donor. They could benefit from desensitization protocols in both pre- and post-transplantation period. Clinical studies are underway to highlight which best desensitization strategies could be assure the best outcome in both heart and kidney transplantation. Although most clinical evidence about desensitization strategies by using anti-CD20 monoclonal antibodies, proteasome inhibitors, anti-CD38 monoclonal antibodies, interleukin-6 blockade, cysteine protease and complement inhibitors, comes from kidney transplantation studies, many of the debated novel concepts can be easily applied to desensitization also in heart transplantation. Here, we discuss the candidates and recipients' management by using most common standard of care and novel therapeutics, desensitization endpoints, and strategies for future studies.

Telemedicine monitoring in the follow-up of kidney transplant recipients: consensus indications from an Italian panel of surgeons and nephrologists after the COVID-19 experience.

The quality of follow-up has clearly emerged as a key factor for long-term kidney graft survival. Currently, many clinics are facing difficulties in delivering optimal surveillance because of the increased number and complexity of kidney transplant recipients, and because of the COVID-19 pandemic. Additional ways of performing follow-up visits are needed and telemedicine has emerged as a tool to strengthen patient care intensity. Six Italian transplant surgeons and nephrologists convened via teleconference to develop a consensual model of video visits for the follow-up of kidney transplant recipients. Issues discussed were: profile of eligible patients; assessments that can be carried out; video visit organization and medical professionals involved; supporting tools and implementation. The video visit was consensually recognized as the most relevant for the follow-up of kidney transplant recipients. Eligible patients should have basic electronic devices and the skills to correctly use them and be in clinically stable condition. With the exception of physical and instrumental examination, and kidney biopsy, all other assessments are feasible during a video visit and can be implemented by specific training and use of supporting tools. The video visit model is simple and adaptable to most transplant patients. It is not intended to replace face-to-face examinations, but is an additional tool for improving the intensity of follow-up of kidney transplant recipients, which can be integrated into current monitoring protocols.

Clinical epigenetics and acute/chronic rejection in solid organ transplantation: An update.

The lack of a precise stratification algorithm for predicting patients at high risk of graft rejection challenges the current solid organ transplantation (SOT) clinical setting. In fact, the established biomarkers for transplantation outcomes are unable to accurately predict the onset time and severity of graft rejection (acute or chronic) as well as the individual response to immunosuppressive drugs. Thus, identifying novel molecular pathways underlying early immunological responses which can damage transplant integrity is needed to reach precision medicine and personalized therapy of SOT. Direct epigenetic-sensitive mechanisms, mainly DNA methylation and histone modifications, may play a relevant role for immune activation and long-term effects (e.g., activation of fibrotic processes) which may be translated in new non-invasive biomarkers and drug targets. In particular, the measure of DNA methylation by using the blood-based "epigenetic clock" system may be an added value to the donor eligibility criteria providing an estimation of the heart biological age as well as a predictive biomarkers. Besides, monitoring of DNA methylation changes may aid to predict acute vs chronic graft damage in kidney transplantation (KT) patients. For example, hypermethylation of genes belonging to the Notch and Wnt pathways showed a higher predictive value for chronic injury occurring at 12 months post-KT with respect to established clinical parameters. Detecting higher circulating cell-free DNA (cfDNA) fragments carrying hepatocyte-specific unmethylated loci in the inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4), insulin like growth factor 2 receptor (IGF2R), and vitronectin (VTN) genes may be useful to predict acute graft injury after liver transplantation (LT) in serum samples. Furthermore, hypomethylation in the forkhead box P3 (FOXP3) gene may serve as a marker of infiltrating natural Treg percentage in the graft providing the ability to predict acute rejection events after heart transplantation (HTx). We aim to update on the possible clinical relevance of DNA methylation changes regulating immune-related pathways underlying acute or chronic graft rejection in KT, LT, and HTx which might be useful to prevent, monitor, and treat solid organ rejection at personalized level.

Metabolic Complications and Kidney Transplantation: Focus on Glycaemia and Dyslipidaemia.

Post-transplant diabetes mellitus (PTDM) and dyslipidaemia are the most common metabolic complications in kidney transplant recipients (KTR). They are associated with a higher risk of lower graft function and survival, as well as an increased risk of cardiovascular disease (CVD). The aim of this review is to provide current data on the epidemiology, pathophysiology and optimal management of these two principal metabolic complications in KTR. Several risk factors in this metabolic milieu are either already present or emerge after renal transplantation, such as those due to immunosuppressive therapy. However, the exact pathogenic mechanisms have not been fully elucidated. Awareness of these disorders is crucial to estimate CVD risk in KTR and optimize screening and therapeutic strategies. These include lifestyle (preferably according to the Mediterranean pattern) and immunosuppressive regimen modification, as well as the best available anti-diabetic (insulin or oral hypoglycaemic agents) and hypolipidaemic (e.g. statins) regimen according to an individual's metabolic profile and medical history.

Prolonged Delayed Graft Function Due to an Extensive Renal Graft Subcapsular Hematoma: Is Conservative Management Justified?

A 62-year-old male patient with diabetes underwent deceased-donor kidney transplant at our transplant unit. At reperfusion, a small and clinically not significant subcapsular hematoma was noted. The patient's postoperative course was characterized by delayed graft function since the beginning but was further complicated on postoperative day 6 by evidence (shown at daily Doppler ultrasonography) of a wide increase of the hematoma. The hematoma, which was just visible before, was now leading to graft compression because it covered up to two-thirds of the cortical surface. The patient showed no hemo-dynamic instability and showed no significant drop in hemoglobin values. Capsulotomy was not performed because it was deemed too risky. The patient was given strict follow-up with Doppler ultrasonography and high-resolution imaging techniques (magnetic resonance imaging and computed tomography scan). In the following days, spontaneous resolution of the hematoma and progressive improvement of Doppler findings were observed, which preceded full recovery of graft function. Conservative management, in hemodynamically stable patients, seems to be a valid approach of this condition. By avoiding surgery or other interventional procedures, a conservative approach allows reduced risk of further complications. Strict monitoring with Doppler ultrasonography is a valid tool for follow-up, along with high-resolution imaging techniques such as magnetic resonance imaging and computed tomography to confirm diagnosis.

Effect of Single Sensitization Event on Human Leukocyte Antigen Alloimmunization in Kidney Transplant Candidates: A Single-Center Experience.

OBJECTIVES: Human leukocyte antigen alloimmunization is caused by exposure to HLA antigens through transfusion, pregnancy, or transplant. Our study objective was to present the rate of positivity of anti-HLA antibody considering the effects of a single sensitization event in kidney transplant candidates at our center. MATERIALS AND METHODS: Our study reviewed 606 kidney transplant candidates. Patient sera were analyzed using Luminex xMAP technology. Panel reactive antibody positivity rates and antibody strengths in patients were analyzed according to a single sensitization event. RESULTS: Our findings showed 246 patients (40.6%) with a panel reactive antibody > 0, of which 97 (39.4%) were sensitized from a single event, 119 (48.4%) were sensitized by multiple events, and 30 (12.2%) had no known sensitizing event. Considering patients sensitized by a single event with a panel reactive antibody > 0, we found that 25.8% had received transplant only, 49.5% had previous pregnancy only, and 24.7% had received transfusion only. The strength of antibodies was significantly higher in patients with previous transplant procedures than in those with transfusion for HLA-A (P < .01), HLA-B (P < .05), HLA-C (P < .05), HLA-DR (P < .001), HLA-DQ (P < .05), and HLA-DP (P < .05). Similarly, we observed significantly higher median fluorescence intensity values for HLA-A, -DR, -DQ, and -DP loci in patients with a previous transplant procedure versus pregnancy. The strength of antibodies against HLA-DR was significantly higher in patients with a previous pregnancy compared with those with transfusion (P < .01). CONCLUSIONS: This study documents the profile of HLA alloimmunization in kidney transplant candidates. In particular, transplant procedures appear to have a greater immunologic impact, followed by pregnancy and transfusion. Our data confirm and are in accordance with those of several studies in which the sensitization events were associated with higher prevalence of anti-HLA antibodies.

HLA-G and anti-HCV in patients on the waiting list for kidney transplantation.

PURPOSE: Human leukocyte antigen (HLA)-G is a non-classic major histocompatibility complex HLA class I molecule. HLA-G may have tolerogenic properties which are linked to epigenetic-sensitive pathways. There is a correlation of sHLA-G levels and graft acceptance in transplantation studies. There are previous data on correlation of sHLA-G with graft rejection as well as with viral infections such as hepatitis C virus (HCV) in kidney transplanted patients. Here, we report the sHLA-G expression in patients on the waiting list for kidney transplantation, with and without anti-HCV compared to a control group. METHODS: Serum of 67 patients on the waiting list for kidney transplantation (n = 43 with anti-HCV and n = 24 without anti-HCV) was analyzed. Among these patients, n = 39 were on the waiting list for the first transplantation, while n = 28 were patients who returned in the list. The control group included n = 23 blood donors with anti-HCV (n = 13) and without anti-HCV (n = 10). RESULTS: The expression of sHLA-G was significantly lower in the control group (39.6 ±â€¯34.1 U/ml) compared to both - patients on the waiting list for the first transplantation (62.5 ±â€¯42.4 U/ml, p=0.031) and patients who returned in the list (76.7 ±â€¯53.9 U/ml, p=0.006). No significant differences were observed in all anti-HCV positive groups. A positive linear correlation between sHLA-G and TNF-α, and patient age was observed. CONCLUSIONS: Serum sHLA-G values were significantly increased in both - patients on the waiting list for the first transplantation and patients who returned in the list, as compared to control group. Our findings confirm the key tolerogenic role of sHLA-G levels as epigenetic-related marker for measuring the state of kidney allograft acceptance.

[Surgical overview on kidney and pancreas transplantation]. / Problemi chirurgici nel trapianto di rene e di pancreas - Position paper.

The main purpose of this paper, written by a group of Italian expert transplant surgeons, is to provide clinical support and to help through the decision-making process over pre-transplant surgical procedures in potential kidney recipients, as well as selection of pancreas transplant candidates and perioperative management of kidney recipient. Current topics such as different approaches in minimally invasive donor nephrectomy, methods of graft preservation and treatment of failed allograft were addressed.

The impact of vitamin D deficiency on patients undergoing kidney transplantation: focus on cardiovascular, metabolic, and endocrine outcomes.

Vitamin D deficiency is common among kidney transplant (KT) recipients because of reduced sunlight exposure, low intake of vitamin D, the immunosuppressive drug regimen administered, and steroid therapy. Glucocorticoids regulate expression of genes coding for enzymes that catabolize vitamin D, further reducing its level in serum. Although vitamin D primarily regulates calcium homeostasis, vitamin D deficiency is associated with the risk of several diseases, such as diabetes mellitus and tuberculosis. Aim of this review is to highlight endocrine and metabolic alterations due to the vitamin D deficiency by evaluating the mechanisms involved in the development of KT-related disease (cardiovascular, bone mineral density, and new-onset diabetes after transplantation). Next, we review evidence to support a link between low vitamin D status and KT-related diseases. Finally, we briefly highlight strategies for restoring vitamin D status in KT patients.

New-onset diabetes mellitus: predictive factors and impact on the outcome of patients undergoing liver transplantation.

Liver transplantation (LT) for hepatocellular carcinoma (HCC) is the treatment of choice for patients with tumor characteristics within the Milan criteria associated with Child B or C cirrhosis. LT provides the best cure for both the tumor and the cirrhosis. There have been several emerging reports that new-onset diabetes mellitus (NODM) after transplantation (NODAT) is one of the most negative predictive factors for low survival rate and related co-morbidities. Little is known about the onset of NODM in post-transplant patients and, overall, whether the pathogenesis of NODM differs from that known for the general population. Principally, it is still unknown whether NODAT is related to the primary hepatic disease, the surgical procedures, immunosuppressive treatments, or is it due to the donor liver. This review will focus on the identification of factors, in the setting of LT, which may lead to the development of NODM. Early prevention of these factors may abate the incidence of NODM and positively impact survival rate, and thus ameliorate the worsening of cardiovascular risk factors which usually occur after LT.

Association between human leukocyte antigen class I and II alleles and hepatitis C virus infection in high-risk hemodialysis patients awaiting kidney transplantation.

Recent evidences have shown that several host genetic factors influence susceptibility or protection to hepatitis C virus (HCV) infection. There are controversial data regarding the associations of human leukocyte antigens (HLA) and the clearance or progression of HCV. The aim of this study was to investigate whether particular HLA molecules were associated with HCV infection in recipients awaiting kidney transplantation considered at high-risk to infection due to protracted hemodialysis treatment. To this purpose, 301 kidney recipients with HCV infection and 1103 uninfected recipients were examined for HLA class I and II molecules. In our case-control study, HLA-A(*)26 is positively associated with HCV infection while HLA-A(*)29, -B(*)40 and -DRB1(*)01 are negatively associated with HCV infection. Multiple logistic regression analysis demonstrated that age (OR = 1.02; 95% CI = 1.01-1.04; p < 0.00), HLA-A(*)26, -A(*)29, -B(*)40 and -DRB1(*)01 [(OR = 1.54; 95% CI = 1.03-2.30; p = 0.03); (OR = 0.50; 95% CI = 0.26-0.99; p = 0.05); (OR = 0.42; 95% CI = 0.23-0, 7; p = 0.01); (OR = 0.62; 95% CI = 0.41-0, 94; p = 0.03); respectively] are independent predictors of HCV infection. Our results suggest that particular HLA molecules, as host genetic factors, may have a relationship with susceptibility or protection to HCV infection also in recipients awaiting kidney transplantation.

New-onset diabetes after kidney transplantation: prevalence, risk factors, and management.

New-Onset Diabetes After Transplantation (NODAT) is an increasingly recognized severe metabolic complication of kidney transplantation causing lower graft function and survival and reduced long-term patient survival mainly due to cardiovascular events. The real incidence of NODAT after kidney transplantation is difficult to establish, because different classification systems and definitions have been employed over the years. Several risk factors, already present before or arising after transplantation, in particular the employed immunosuppressive regimens, have been related to the development of NODAT. However the responsible pathogenic mechanisms are still far to be perfectly known. Awareness of NODAT and of the NODAT-related factors is of paramount importance for the clinicians in order to individuate higher risk patients and arrange screening strategies. The risk of NODAT can be reduced by planning preventive measures and by tailoring immunosuppressive regimens according to the patient characteristics. Once NODAT has been diagnosed, the administration of specific anti-hyperglycemic therapy is mandatory to reach a tight glycemic control, which contributes to significantly reduce posttransplant mortality and morbidity.