Physical Exercise in Kidney Renal Recipients: Where Have We Come?

BACKGROUND: Kidney transplantation constitutes the most effective therapeutic option for patients suffering from end-stage renal disease but remains burdened by a high incidence of cardiovascular disease. To date, exercise is an important preventive strategy that has been underestimated; in kidney transplant patients, exercise programs lead to an improvement in cardiorespiratory performance, muscle strength, arterial stiffness, and patients' quality of life perception. SUMMARY: The nephrology and transplant community have moved from generic suggestions to specific indications regarding frequency, intensity, time, type, volume, and progression of physical exercise both in the pre- and posttransplant phase. The latest guidelines from the World Health Organization for patients with chronic conditions propose a combination of aerobic, muscle-strengthening, and multicomponent exercises (e.g., balance) to improve health. Based on recent evidence, a combined exercise program (aerobic and strength exercise) is largely proposed to kidney transplant recipients. Aerobic exercise should be performed at an intensity >60% of theoretical maximum heart rate or maximum oxygen uptake possibly every day, and strength training should be performed at a >60% the estimate single maximum repetition, at least 2 times per week. KEY MESSAGES: Physical exercise should be personalized in relation to the patient's baseline performance; increases must be progressive and gradual. Regular physical activity should also be recommended to patients awaiting for a transplant. Eventually, organizational models based on a network of nephrology units, transplant centers, sports medicine centers, and fitness center or outdoor gym are essential elements for overcoming the logistical barriers for prescribing and carrying out regular physical activity.

An early start of West Nile virus seasonal transmission: the added value of One Heath surveillance in detecting early circulation and triggering timely response in Italy, June to July 2018.

In Italy, the 2018 West Nile virus transmission season started early with a high number of cases reported. One-Health surveillance, within the Italian West Nile national preparedness and response plan, detected viral circulation 9 days before symptom-onset of the first confirmed human case; triggering timely implementation of blood and transplant safety measures. This is an example of how functional coordination allows health authorities to use early warning triggers from surveillance systems to implement preventive measures.

Physical activity in solid organ transplant recipients: preliminary results of the Italian project.

BACKGROUND/AIMS: The role of physical activity in transplanted patients is often underestimated. We discuss the Italian National Transplant Centre experience, which started in 2008 studying transplanted patients involved in sports activities. The study was then developed through a model of cooperation between surgeons, sports physicians and exercise specialists. METHODS: A multicentre study was realized in 120 transplanted patients of which 60 treated with supervised physical activity (three sessions/week of aerobic and strengthening exercises) and 60 controls. We present the results of the first 26 patients (16 males, 10 females; 47.8 ± 10.0 years; 21 kidney, 5 liver transplanted; time from transplant 2.3 ± 1.4 years) who completed 12 months of supervised physical activity. RESULTS: Data showed an increase of peak aerobic power (t=4.535; P<0.01) and maximum workload (t=4.665; P<0.01) in the incremental cycling test. Maximum strength of knee extensors (t=2.933; P<0.05) and elbow flexors (t=2.450; P<0.05), and the power of lower limb (t=2.303; P<0.05) significantly increases. Health Related Quality of Life showed a significant improvement. Serum creatinine (1.4 ± 0.5 vs 1.3 ± 0.4 mg/dL) and proteinuria (0.10 ± 0.14 vs 0.08 ± 0.08 gr/dL) were stable. CONCLUSION: These preliminary results confirm the positive effects of supervised physical exercise. It can be considered as an input to promote other detailed exercise protocols.

Hepatitis B-core antibody positive donors in liver transplantation and their impact on graft survival: evidence from the Liver Match cohort study.

BACKGROUND & AIMS: The appropriate allocation of grafts from HBcAb positive donors in liver transplantation is crucial, yet a consensus is still lacking. METHODS: We evaluated this issue within Liver Match, a prospective observational Italian study. Data from 1437 consecutive, first transplants performed in 2007-2009 using grafts from deceased heart beating donors were analyzed (median follow-up: 1040 days). Of these, 219 (15.2%) were HBcAb positive. Sixty-six HBcAb positive grafts were allocated to HBsAg positive and 153 to HBsAg negative recipients. RESULTS: 329 graft losses occurred (22.9%): 66 (30.1%) among 219 recipients of HBcAb positive grafts, and 263 (21.6%) among 1218 recipients of HBcAb negative grafts. Graft survival was lower in recipients of HBcAb positive compared to HBcAb negative donors, with unadjusted 3-year graft survival of 0.69 (s.e. 0.032) and 0.77 (0.013), respectively (log-rank, p=0.0047). After stratifying for recipient HBsAg status, this difference was only observed among HBsAg negative recipients (log rank, p=0.0007), 3-year graft survival being excellent (0.88, s.e. 0.020) among HBsAg positive recipients, regardless of the HBcAb donor status (log rank, p=0.4478). Graft loss due to de novo HBV hepatitis occurred only in one patient. At Cox regression, hazard ratios for graft loss were: MELD (1.30 per 10 units, p=0.0002), donor HBcAb positivity (1.56, p=0.0015), recipient HBsAg positivity (0.43, p <0.0001), portal vein thrombosis (1.99, p=0.0156), and DRI (1.41 per unit, p=0.0325). CONCLUSIONS: HBcAb positive donor grafts have better outcomes when transplanted into HBsAg positive than HBsAg negative recipients. These findings suggest that donor HBcAb positivity requires more stringent allocation strategies.

Liver transplantation from hepatitis B surface antigen positive donors: a safe way to expand the donor pool.

BACKGROUND & AIMS: The main limitation of orthotopic liver transplantation (OLT) is the scarcity of available donor organs. A possibility to increase the organ pool is to use grafts from hepatitis B virus surface antigen (HBsAg) positive donors, but few data are currently available in this setting. We assessed the clinical, serovirological, and immunological outcomes of liver transplant from HBsAg positive donors in a single centre study. METHODS: From 2005 to 2009 10 patients underwent OLT from HBsAg positive donors, for HBV-related disease (n=6) or HBV-unrelated disease (n=4). The median follow-up was 42 months (range 12-60). All recipients were HBcAb positive and were given antiviral prophylaxis. RESULTS: Patients transplanted for HBV-related disease never cleared HBsAg. Two HBsAg negative patients never tested positive for HBsAg, whereas the others experienced an HBsAg appearance, followed by spontaneous production of anti-HBs, allowing HBsAg clearance. No patient ever had any sign of HBV hepatitis. HBV replication was effectively controlled by antiviral therapy. The immunologic sub-study showed that a most robust anti-HBV specific T cell response was associated with the control of HBV infection. CONCLUSIONS: OLT from HBsAg positive donors seems to be a safe procedure in the era of highly effective antiviral therapy.

Cord blood stem cell banking: a snapshot of the Italian situation.

BACKGROUND: In Italy, the law does not permit the setting up of private banks to preserve cord blood (CB) stem cells for personal use. However, since 2007 the right to export and preserve them in private laboratories located outside Italy has existed, and an increasing number of women are requesting this collection of umbilical CB at delivery to enable storage of stem cells for autologous use. STUDY DESIGN AND METHODS: Since private banks recruit clients mainly via the Internet, we examined the content of 24 Italian-language websites that offer stem cells storage (from CB or amniotic fluid), to assess what information is available. RESULTS: We found that the majority of private banks give no clear information about the procedures of collection, processing, and banking of CB units and that the standards offered by private CB banks strongly differ in terms of exclusion or acceptance criteria from the public banks. These factors may well influence the overall quality of the CB units stored in private CB banks. Of note, during the period 2007 to 2009, the number collected for autologous use did not create a downward trend on the number of units stored in public CB banks for allogeneic use. CONCLUSION: CB is a valuable community resource but expectant parents should be better informed as to the quality variables necessary for its storage, both by institutions and by professionals. Currently, most of the advertising is insufficient to justify the expense and the hopes pinned on autologous use of CB stem cells.

Current situation of donation after circulatory death in European countries.

The aim of the present study was to describe the current situation of donation after circulatory death (DCD) in the Council of Europe, through a dedicated survey. Of 27 participating countries, only 10 confirmed any DCD activity, the highest one being described in Belgium, the Netherlands and the United Kingdom (mainly controlled) and France and Spain (mainly uncontrolled). During 2000-2009, as DCD increased, donation after brain death (DBD) decreased about 20% in the three countries with a predominant controlled DCD activity, while DBD had increased in the majority of European countries. The number of organs recovered and transplanted per DCD increased along time, although it remained substantially lower compared with DBD. During 2000-2008, 5004 organs were transplanted from DCD (4261 kidneys, 505 livers, 157 lungs and 81 pancreas). Short-term outcomes of 2343 kidney recipients from controlled versus 649 from uncontrolled DCD were analyzed: primary non function occurred in 5% vs. 6.4% (P = NS) and delayed graft function in 50.2% vs. 75.7% (P < 0.001). In spite of this, 1 year graft survival was 85.9% vs. 88.9% (P = 0.04), respectively. DCD is increasingly accepted in Europe but still limited to a few countries. Controlled DCD might negatively impact DBD activity. The degree of utilization of DCD is lower compared with DBD. Short-term results of DCD are promising with differences between kidney recipients transplanted from controlled versus uncontrolled DCD, an observation to be further analyzed.

The critical pathway for deceased donation: reportable uniformity in the approach to deceased donation.

The critical pathway of deceased donation provides a systematic approach to the organ donation process, considering both donation after cardiac death than donation after brain death. The pathway provides a tool for assessing the potential of deceased donation and for the prospective identification and referral of possible deceased donors.

Facial transplantation: from the early trials to ethical and clinical guidelines. Commentary.

Facial transplantation is a complex technique that involves a number of risks. However, although it is not a lifesaving transplant, for individuals in dramatic conditions due to severe facial disfigurements, it constitutes the only possibility of recovering an acceptable quality of life. For this reason, even from an ethical point of view, it is considered an important therapeutic resource, provided it is conducted in rigorously-controlled conditions.

Organ Transplantation From Nonstandard Risk Donors: Midway Between Rigid and Flexible Rules.

In order to bridge the gap between available organs and patients needing transplants, donor selection criteria for donors are increasingly being extended; the possibility of using organs from nonstandard risk donors has been introduced in many countries. This clearly poses considerable ethical issues that should be analyzed and taken into consideration by the competent bodies and institutions. In this article, we illustrate the Italian situation regarding the possibility of using organs from anti-hepatitis C virus (HCV) and HCV RNA-positive donors (anti-HCV+ve) in negative recipients (healthy subjects who have never come into contact with the hepatitis C virus) in light of the availability of new direct-acting antiviral drugs (DAAs) for hepatitis C treatment. We discuss the motivations behind the both favorable opinions of the Ethics Committee of the Italian National Institute of Health (Istituto Superiore di Sanità) and the Italian National Bioethics Committee (Comitato Nazionale per la Bioetica) discussing the main implications from an ethical point of view.

No metagenomic evidence of tumorigenic viruses in cancers from a selected cohort of immunosuppressed subjects.

The possible existence of yet undiscovered human tumorigenic viruses is still under scrutiny. The development of large-scale sequencing technologies, coupled with bioinformatics techniques for the characterization of metagenomic sequences, have provided an invaluable tool for the detection of unknown, infectious, tumorigenic agents, as demonstrated by several recent studies. However, discoveries of novel viruses possibly associated with tumorigenesis are scarce at best. Here, we apply a rigorous bioinformatics workflow to investigate in depth tumor metagenomes from a small but carefully selected cohort of immunosuppressed patients. While a variegated bacterial microbiome was associated with each tumor, no evidence of the presence of putative oncoviruses was found. These results are consistent with the major findings of several recent papers and suggest that new human tumorigenic viruses are not common even in immunosuppressed populations.

The "New Charter for Health Care Workers" and the ethics of organ donation and transplantation. Commentary.

Comparison is made between the proposals put forward by the "New Charter for Health Care Workers" in the matter of organ transplants and other models of bioethics. The personalist approach adopted by the New Charter is illustrated and the proposals contained in it are finally placed alongside the reference ethical principles underlying the Italian transplant network: they are found to be fully in agreement.

A population-based study of cancer incidence in solid organ transplants from donors at various risk of neoplasia.

A population-based cohort study of recipients of organs from donors with a recognized history or active cancer has been conducted by linking the Italian National Registry of Transplanted Patients and the National Registry of Donors with Neoplasia Risk. Between 2002 and 2004, 8,198 solid organ transplants have been performed in Italy, 108 of them with organs from 59 cadaveric donors with various risk of neoplasia. There were two reported cases of nonmelanoma skin cancer during the follow up of the transplanted patients, which lasted 27.6+/-11.3 months (234 patient-years). In our study, recipients of organs from donors with various degree of neoplasia risk are exposed to a low risk of cancer transmission.

Liver transplantation in Italy: analysis of risk factors associated with graft outcome.

OBJECTIVE: To analyze the graft outcome after liver transplantation in Italy in the years 1995 to 2000. METHODS: We performed a longitudinal study with follow-up at 3 months, 1 year, 3 years, and 5 years on 1987 liver grafts. The effect of several variables on graft survival was also analyzed. RESULTS: Several variables affect graft survival: Donor and recipient older age, gender mismatching, prolonged cold ischemia time, acute hepatic necrosis, and retransplantation are reported to significantly affect liver graft survival. Donors older than 60 years show a relative risk of 1.59 (95% CI, 1.23-2.05) compared with donors with an age between 19 and 60 years; recipients older than 50 years show a relative risk of 1.29 (95% CI, 1.04-1.60) compared with recipients aged 19 to 50 years. A cold ischemia time of 12 hours or longer doubled the risk of failure (relative risk = 2.01, 95% CI, 1.36-2.96) compared with a cold ischemia time of less than 6 hours. CONCLUSIONS: The results show that the overall quality of liver transplantation in Italy is satisfying and comparable to the outcome reported by international registries. Follow-up studies on large numbers of liver transplants are useful to define predictors of outcome, and subsequently modify the criteria for organ allocation.

Analysis of the complex effect of donor's age on survival of subjects who underwent heart transplantation.

BACKGROUND: Only half of the patients waiting for a heart transplant undergo surgery, whereas several patients continue to die while on the waiting list. Donor organ availability still represents a major problem with respect to reducing the length of the cardiac transplant waiting list. One option to improve donor availability is the use of so called "marginal donors." The aims of the present study are to analyze the short-mid term survival of cardiac transplanted patients in Italy, and investigate the effect of donor age on prognosis. METHODS: A prospective cohort study including all adult patients who underwent heart transplantations in Italy was used to analyze the main factors contributing to organ survival. RESULTS: From 1995-2002, 2,504 adult subjects underwent a cardiac transplant, and were followed up for a period of 540.9 days. Overall, 1-year graft survival was 83.1%. Organs from donors older than 55 years had a lower survival than organs from younger donors. By multivariate analysis, both donor's and recipient's age seem to be important determinants of graft survival. A more sophisticated analysis shows that the trend of the risk of graft failure according to donor's age is not linear, with a peak at age 47.3 years, and differs according to sex. CONCLUSIONS: Results from the present analysis suggest that the association between heart transplant survival and donor's age is not a linear one, but follows a complex mathematical model, with influences of sex, at least in our sample.

Genomic allelotyping for distinction of recurrent and de novo hepatocellular carcinoma after orthotopic liver transplantation.

Distinction between recurrent and de novo hepatocellular carcinoma (HCC) after orthotopic liver transplantation (OLT) bears important clinical and therapeutic implications. Techniques for molecular profiling of clinically suspected de novo and recurrent HCC are required since the histological/clinical discrimination of donor vs. recipient tumor origin is difficult. Multiple PCR amplification of 16 highly polymorphic short tandem repeat (STR) DNA sequences (routinely used for paternity and forensic assays) was applied in two patients who developed a second HCC after OLT. In both patients the technique provided reliable evidence that the two second HCC were recurrences of the primary tumor. Multiple STR genetic allelotyping is an effective tool for clear-cut discrimination of donor/recipient origin of a second HCC after OLT. Its application could be of great therapeutic relevance for such OLT patients.

Kidney graft survival in Italy and factors influencing it.

PURPOSE: National registry data are often a suitable basis for examination of transplant outcomes. Using data supplied by the Italian National Transplant Registry, established in 1995, we performed the first nationwide analysis of this kind. METHODS: A retrospective analysis of 4893 recipients of cadaveric kidneys transplanted in all Italian centers from 1995 through 2000 was done to study 5-year graft survival. The association between some donor and recipient variables and outcomes in renal transplantation was analyzed. Graft survival was 93% at 3 months, 89% at 1 year, 82% at 3 years, and 80% at 5 years after transplantation. RESULTS: A significant association between graft survival and donor age (old vs young, relative risk [RR] = 1.62, 95% CI 1.27-2.06) and recipient age (old vs young, RR = 1.25, 95% CI 1.02-1.53). Graft survival was also associated with cold ischemia time (24-36 hours, RR= 1.39, 95% CI 1.05-1.85 and >36 hours, RR= 1.94, 95% CI 1.32-2.86 vs 0-24 hours) and donor/recipient sex mismatch (female/male vs male/male, RR= 1.50, 95% CI 1.17-1.93). CONCLUSION: The quality of kidney transplantation in Italy is satisfactory and is comparable to that in other developed countries. Furthermore, our experience confirms that both donor and recipient factors are major determinants of renal allograft function.

Incidence of carbapenem-resistant gram negatives in Italian transplant recipients: a nationwide surveillance study.

BACKGROUND: Bacterial infections remain a challenge to solid organ transplantation. Due to the alarming spread of carbapenem-resistant gram negative bacteria, these organisms have been frequently recognized as cause of severe infections in solid organ transplant recipients. METHODS AND FINDINGS: Between 15 May and 30 September 2012 we enrolled 887 solid organ transplant recipients in Italy with the aim to describe the epidemiology of gram negative bacteria spreading, to explore potential risk factors and to assess the effect of early isolation of gram negative bacteria on recipients' mortality during the first 90 days after transplantation. During the study period 185 clinical isolates of gram negative bacteria were reported, for an incidence of 2.39 per 1000 recipient-days. Positive cultures for gram negative bacteria occurred early after transplantation (median time 26 days; incidence rate 4.33, 1.67 and 1.14 per 1,000 recipient-days in the first, second and third month after SOT, respectively). Forty-nine of these clinical isolates were due to carbapenem-resistant gram negative bacteria (26.5%; incidence 0.63 per 1000 recipient-days). Carbapenems resistance was particularly frequent among Klebsiella spp. isolates (49.1%). Recipients with longer hospital stay and those who received either heart or lung graft were at the highest risk of testing positive for any gram negative bacteria. Moreover recipients with longer hospital stay, lung recipients and those admitted to hospital for more than 48h before transplantation had the highest probability to have culture(s) positive for carbapenem-resistant gram negative bacteria. Forty-four organ recipients died (0.57 per 1000 recipient-days) during the study period. Recipients with at least one positive culture for carbapenem-resistant gram negative bacteria had a 10.23-fold higher mortality rate than those who did not. CONCLUSION: The isolation of gram-negative bacteria is most frequent among recipient with hospital stays >48 hours prior to transplant and in those receiving either heart or lung transplants. Carbapenem-resistant gram negative isolates are associated with significant mortality.

Strategies for evaluation of suitable donors: Italian experience.

Italy was lacking standardised procedures for donor safety evaluation. We developed practice guidelines, while a panel of experts coordinated by the National Transplant Centre, is available 24 hours a day to support decisions in difficult cases. The guidelines identify five levels of risk and give recommendations for the utilization of donors with HBV and HCV infections as well as for malignancies with negligible or very low risk of transmission. In conclusion we aim to standardize the process of donor evaluation across Italy, to increase the pool of utilised donors and to reduce the risk of communicable disease transmission.

Donor Action program in the Emilia-Romagna region of Italy.

CONTEXT: The high demand for organs for transplantation necessitates enhancement of organ procurement activity worldwide. OBJECTIVE: To detect critical areas in the organ donation process and to assess whether careful monitoring of deaths in each intensive care unit could improve rates of identification of brain death. DESIGN: Records of patients who died in intensive care units in the Emilia-Romagna region between July 1, 1998 and June 30, 2000 were reviewed through the Donor Action program. RESULTS: Of the 2469 patients who died during the period studied, 1010 (40.9%) had severe brain damage, as indicated by a score of 3 on the Glasgow coma scale. A total of 857 patients with severe brain damage who had spent more than 6 hours in the intensive care unit (34.7% of all deaths) were considered as potential donors. Signs of brain death were observed in 383 (44.7%) of the 857 patients who died. Rates of identification of brain death increased from 36% to 55% during the study period. CONCLUSION: Considering that the characteristics of the study population had not changed, we believe that the Donor Action program was an important factor leading to the observed improvement in identification of brain death.