Dzieci jako dawcy szpiku

Donors are key component in transplantation. There are no transplantations without donors. As in any medical procedure, donors are subject to risk of medical complications. An increasing number of stem cell transplantations is observed continuously. In the middle of 2013, a total number of almost 22 million unrelated donors have been registered worldwide, including 440 thousand Polish citizens. In 2012, the ratio of transplants from Polish donors reached 50% among all unrelated transplants performed in our country. Before the stem cell collection, the donor has to be assessed for risk of disease transmission to recipient, safety of stem cell collection for donor and full understanding of stem cell donation. There are 2 methods of stem cell collection: bone marrow harvest and peripheral blood stem cell apheresis. Bone marrow harvest is a standard of care in children, while peripheral blood stem cell collection in adults. Donation of stem cell is a safe procedure for donor. Nevertheless, mild adverse events are relatively frequent, however disappearing in most cases within several days after the collection. The number of requests for stem cell donation is increasing, also for the second or third donation from the same donor. It results in growing medical experience and donors’ safety. Although medical progress and standards of patients care contribute to systematic decrease of adverse events for donors, the risk still exists. This should not be the reason for anyone to withhold an agreement for stem cell donation for the sick patient waiting for stem cell transplantation. This analysis presents new insight on safety and prophylaxis of risk of adverse events in children undergoing bone marrow harvest.     

Bone marrow transplantation for severe aplastic anemia in children

For young adults and children who have a bone marrow donor who is a genotypic or phenotypic sibling match, bone marrow transplantation is now the preferred treatment for severe aplastic anemia. For those who lack such a matched donor, use of matched unrelated donors and family member donors who are mismatched for a single HLA antigen have been successful and appear to be the treatment of choice. Patients lacking either of these alternatives should receive antilymphocyte globulin, either alone or combined with cyclosporine as a first step. Although the success rate of marrow transplants in our series using mismatched family donors is similar to that following treatment with antilymphocyte globulin, several caveats must be kept in mind. First, the results reported with use of alternative donors must be confirmed with study of larger numbers of patients and longer follow-up. Second, the preparative regimen given prior to bone marrow transplantation destroys the patient's residual bone marrow, whereas antilymphocyte globulin cyclosporine A and androgens do not. The sequence of immunosuppression followed by transplantation with alternative donor marrow should produce greater long-term hematopoietic improvement. Unfortunately, when marrow transplant follows one or more courses of immunosuppressive therapy, nonengraftment is then a problem because of sensitization to blood cell antigens. It should also be kept in mind that studies done in children, especially in those younger than 6 years old, show that these patients respond better to transplantation than to treatment regimens not including marrow transplantation. Therefore, for the child with severe aplastic anemia, every effort should be made to identify a suitable bone marrow donor. Finally, we need to determine the specific components of the conditioning regimen and the constitution of the donor marrow necessary for engraftment and to minimize potential long-term complications, and there should be only a tolerable degree of graft-versus-host disease. Many of the transplant-related problems that plagued us in the 1970s have still not been fully resolved, but many have shown improvement. As we enter the 1990s, increasing the pool of marrow donors for patients with severe aplastic anemia who lack an HLA-matched sibling will continue to be a top priority for research.     

Cord blood transplant: Current and future issues

Cord blood as the source of hematopoietic stem cells has several advantages over bone marrow cells for transplant purpose. It is readily available, and causes no physical harm or inconveniences to the donor in the processing of harvesting cells. Waiting time between initiating the search and the time to transplant from an unrelated donor is much shorter with cord blood than with unrelated donor bone marrow. The incidence of graft-versus-host diseases is much less. Because of these advantages, cord blood has been increasingly used as the source of stem cells. As of this writing, more than 200 cord blood transplants have been done in patients with hematological malignancies, solid tumors, hematological diseases, immunodeficiency syndromes, and metabolic diseases. One of the limitations inherent in the cord blood is its limited number of hematopoietic stem cells. Thus it has been primarily used for pediatric patients, though more recently, adult patients also have been transplanted with cord blood as people have become more experienced in harvesting cord blood thus yielding a large number of stem cells in a given specimen. Efforts have been made to amplify stem cellsin vitro following harvesting cord blood stem cells, so that adult recipients also would routinely benefit from this resource. Cord blood lymphocytes are functionally “naive”, do not generate vigorous mixed lymphocyte culture reactivities. The low incidence of graft-versus-host disease in the recipients of cord blood is due to this particular property. It is highly desirable that the world wide cord blood registry, similar to the international bone marrow registry would be instituted, but there are logistic, ethical and financial problems that need to be resolved. Cord blood is one of the best stem cell sources, and its application is quite wide.     

Factors associated with bone marrow stem cell yield for pediatric allogeneic stem cell transplantation: The impact of donor characteristics

The aim of this study was to investigate the effects of donor characteristics on CD34⁺ cell yield in BM harvest. Between April 2010 and November 2013, consecutive donors who underwent BM harvesting in our BM transplantation unit were retrospectively investigated. Donors were classified into two groups: those who donated BM without mobilization (steady‐state BM donors) and those who received G‐CSF for stem cell mobilization (G‐CSF‐primed BM donors). Donor characteristics (age, gender, race, body weight, BMI, and laboratory factors including donor's leukocyte, platelet, and monocyte) and their relationship with total nuclear cell and CD34⁺ cell numbers has been evaluated. A total of 64 healthy related donors (29 males/35 females, median age 11.2 years; 49 [76.6%] younger than 18 and 36 [56.3%] younger than 12 years) were included in the study. The median CD34⁺ cell yield in the harvest was 0.12×10⁶/L (0.02‐0.21) in SS‐BM donors and 0.18×10⁶/L (0.09‐0.67) in GP‐BM donors (P=.03). Median of CD34⁺ cell count given to recipients was 2.6×10⁶/recipient body weight (1.3‐19.3) in SS‐BM yields and 3.8×10⁶/recipient body weight (1.1‐10.2) in GP‐BM yields, respectively. Multiple regression analysis showed that donor height and pre‐G‐CSF platelet were the most important parameters to obtain a sufficient BM harvest. Our data suggest that the shorter donors and the donors with higher thrombocyte counts may offer more hematopoietic stem cell. The height and thrombocyte count of the donors should be taken into consideration before planning the targeted CD34⁺ cell count especially for pediatric donors.     

The impact of public health service increased risk donors in pediatric liver transplantation

Many transplant programs are reluctant to use organs from deceased donors designated as “PHS increased risk” due to misconceptions regarding the quality of those organs. This study evaluated the impact of PHS increased risk donors on patient and allograft survival in pediatric patients undergoing liver transplantation. Retrospective analysis of the UNOS database from January 2005 through September 2017 revealed 5615 pediatric patients who underwent isolated liver transplantation; of these, 5057 patients received primary isolated liver transplants and 558 patients received isolated liver retransplants. PHS increased risk organs were used in 6.7% and 5.4% of the children receiving primary isolated and retransplant livers, respectively. Cox proportional hazards models adjusted for donor and recipient characteristics determined the relative risk of PHS status on allograft and patient survival. Sicker children (those in ICU [P < .001] and on life support [P = .04]) were more likely to receive PHS increased risk donor organs. There were no differences in overall patient (P = .61) or allograft (P = .68) survival between pediatric patients receiving PHS positive vs PHS negative deceased donor organs; adjusted models also demonstrated no statistically significant differences in patient or allograft survival. Excellent patient and allograft survival can be accomplished with PHS increased risk organs.     

Impact of donor preprocurement cardiac arrest on clinical outcomes in pediatric deceased donor liver transplantation

PPCA has historically been considered detrimental to donor quality in LT, but transplantation of grafts from this group of donors is now routine. Our study aims to evaluate the outcomes associated with use of donors with a history of PPCA in the pediatric population. This study is a single‐center retrospective analysis of all pediatric LTs performed over an 18‐year period. Donors and recipients were stratified by the presence and length of donor PPCA time. Preprocurement donor and post‐transplant recipient laboratory values were collected to assess the degree of ischemic liver injury associated with each donor group. Cox regression analysis was used to compare survival. The records for 130 deceased pediatric LT donors and corresponding recipients were reviewed. There were 73 (56%) non‐PPCA donors and 57 (44%) PPCA donors. Donors that experienced a PPCA event demonstrated a higher median, pretransplant peak alanine aminotransferase (ALT) level (P < .001). When comparing post‐transplant recipient median ALT levels, donors with any PPCA had lower median peak ALT (P = .15) and day 3 ALT (P = .43) levels than the non‐PPCA group. Rates of early graft loss did not differ. The PPCA group with >40 minutes of ischemia had markedly lower survival at 10 years, but this finding did not reach statistical significance. Liver grafts from donors with or without PPCA demonstrated no statistically significant differences in function or survival. A history of donor PPCA alone should not be used as an exclusionary criterion in pediatric liver transplantation.     

Are drowned donors marginal donors? A single pediatric center experience

Drowning, a common cause of death in the pediatric population, is a potentially large donor pool for OLT. Anecdotally, transplant centers have deemed these organs high risk over concerns for infection and graft dysfunction. We theorized drowned donor liver allografts do not portend worse outcomes and therefore should not be excluded from the donation pool. We reviewed our single‐center experience of pediatric OLTs between 1988 and 2015 and identified 33 drowned donor recipients. These OLTs were matched 1:2 to head trauma donor OLTs from our center. A chart review assessed postoperative peak AST and ALT, incidence of HAT, graft and recipient survival. Recipient survival at one year between patients with drowned donor vs head trauma donor allografts was not statistically significant (94% vs 97%, P=.63). HAT incidence was 6.1% in the drowned donor group vs 7.6% in the control group (P=.78). Mean postoperative peak AST and ALT was 683 U/L and 450 U/L for drowned donors vs 1119 U/L and 828 U/L in the matched cohort. These results suggest drowned donor liver allografts do not portend worse outcomes in comparison with those procured from head trauma donors.     

Bone marrow transplantation for hematological disorders—Shiraz experience

Objective : In the past 8 years, 120 cases of hematological disorders were transplanted from the HLA identical donors.Method: Using chemotherapy based conditioning regimen with cyclophosphamide 200 mg/kg and busulfan 15–16 mg/kg, 80 cases of β-thalassemia major and 35 cases of leukemia and five patients with aplastic anemia had received bone marrow transplantation.Result : The five-year-survival in thalassemic group was 72%, for leukemic group (acute and chronic) was 58%, and also for aplastic anemia 65%. Transplantation related mortality was the cause of death in 29 cases. The two major causes of death were acute graft versus host disease and poor medical condition of patients before marrow transplantation.Conclusion : At the present time, allogenic marrow transplantation is curative mode of treatment for many hematological diseases.     

Optimizing the utilization of kidneys from small pediatric deceased donors under 15 kg by choosing pediatric recipients

Currently, most kidneys from small pediatric deceased donors are transplanted into adult recipients (i.e., PTA). However, due to the weight mismatch, there is a high discard rate and a high ratio of EBKTs if adopting PTA. Here, we sought both to optimize utilization of these challenging but scarce donor grafts by selecting pediatric recipients and to characterize the feasibility and efficacy of this PTP allocation strategy. From February 2012 to October 2014, kidneys from 27 infant donors ≤15 kg were procured and distributed to 38 pediatric candidates in our center. The grafts were utilized for EBKT if the donor weighed 2.5–5 kg and for SKT if the donor weighed 5–15 kg, leading to 10 EBKTs and 28 SKTs. The overall utilization rate from small pediatric deceased donors was 94.12%. After a follow‐up of 3–26 months, the graft survival rate was 89.47%, with four graft losses due to vascular thrombosis. Kidneys from low‐body‐weight donors should be applied to pediatric recipients, and the kidneys from infant donors ≥5 kg can be used in single‐kidney‐transplant procedures at experienced centers to optimize utilization.     

Selection of donors for living donor liver transplantation in a single center of a developing country: lessons learned from the first 100 cases

The selection of donors for living donor liver transplantation (LDLT) is one of the most important features in this kind of surgery. The aim of this study is to describe our initial experience in the donor evaluation process. From December 2001 to January 2005, 104 donors were evaluated for 70 recipients (65 potential donors were evaluated for 39 adult recipients, and 39 donors for 31 pediatric recipients). Only 30 donors were able to donate: 13 for the adult group, and 17 for the pediatric one. In general, the utilization rate of potential donors was 28.8% (30/104). For the adult patients, 65 potential donors were seen to perform 13 LDLT, which represents a utilization rate of potential donors of 20%. For the pediatric patients, this rate was 43.6%. The exclusion criteria were clinical in 22 cases (21%), anatomical in 13 cases (13%), psychosocial in nine cases (9%), and others in 12 (12%). Death of recipients led to exclusion 18 of donors (17%). Thirty-three percent of adults and 55% of pediatric recipients who had at least one potential donor to start the evaluation process were able to identify a living donor. In conclusion, the first limit for LDLT is the rigorous donor evaluation.     

Human malignant osteopetrosis: Pathophysiology, management and the role of bone marrow transplantation

Abstract: steopetrosis is a heterogeneous group of diseases characterized by lack of osteoclast function. Osteopetrosis is found spontaneously in most mammalian species and many transgenic animals have been created, but so far no animal model has been found that genetically corresponds to human malignant autosomal recessive osteopetrosis. The only curative treatment for malignant osteopetrosis is bone marrow transplantation. A review of the literature and preliminary data from IBMTR shows that infants transplanted with marrow from an HLA-identical sibling or unrelated volunteer donor have an actuarian five-year survival with a functioning graft of 50–70%, while those transplanted with a T-cell-depleted mismatched marrow have a very poor survival of only about 10%.     

Ten‐year experience of unrelated bone marrow donor transplants in children with malignant and non‐malignant conditions

Children who require a marrow transplant may receive such hematopoietic cells from one of many sources. This study reviews the experience of one center with 58 children who received marrow from unrelated donors over a 10-year period. These children had a variety of malignant and non-malignant diseases. During that time period, only three of these children had failed to meet engraftment criteria. All donor marrow specimens were T-lymphocyte-depleted using an antibody/complement methodology. No difference was demonstrated in outcome between donors who were perfectly HLA-DR DNA matched versus those who were only partially matched. The increased size of various marrow donor registries has increased the number of potential donors available for these patients. The lack of a requirement for perfect matching means that there is an ever-increasing number of donors available. No graft-versus-host disease (GvHD) or grade III-IV GvHD was associated with a poorer outcome. Stable, long-term engraftment with minimal morbidity has been demonstrated in these children as evidenced by stability of survival curves by two years after marrow transplant.     

Pediatrics and donor‐derived disease transmission: The US OPTN experience

PDDTE are tracked by the OPTN Ad Hoc DTAC. Specific evaluation of potential transmissions from pediatric deceased donors or the impact of donor‐derived disease transmissions to pediatric organ recipients has not been previously undertaken. PDDTE reported to the DTAC between 2008 and 2013 were reviewed, characterized as proven, probable, possible, IWDT, unlikely, or excluded for both the whole event and each individual recipient. Pediatric donors and recipients were defined as being 0‐17 years of age. Analysis was undertaken to characterize potential disease transmission from pediatric donors to adult or pediatric recipients and also to evaluate potential transmission from all donors to pediatric recipients. P/P cases were further analyzed. A total of 5238 pediatric deceased US donors accounted for 17 456 organ transplants during the study period; 103 PDDTE reports arose from these donors (2.0%). PDDTE were characterized as P/P (15%), possible (13%), IWDT (9%), unlikely, and excluded (63%). Disease was transmitted to 22 of 54 potentially exposed (adult and pediatric) recipients with six attributable deaths. An infectious pathogen accounted for 13/15 of the P/P PDDTE associated with pediatric donors, affecting 19 of 50 potentially exposed recipients and resulting in five deaths. Four separate viral pathogens from six donors accounted for P/P transmissions to 11 recipients with the unanticipated transmission of CMV most common. No pediatric donor transmitted HIV, HBV, or HCV. Bacteria, fungi, and parasites accounted for three (all staphylococci), three (Zygomycetes and Histoplasma), and two (both Toxoplasma) P/P transmissions from seven donors, respectively. From the recipient side, 11/11,188 pediatric recipient deceased and living donor transplants during the study period were associated with a P/P PDDTE (<0.1%) with infectious pathogens accounting for 9/11 P/P events. Infections were split among pathogen categories (bacteria 2, viruses 3, parasites 3, and fungi 1). Reporting rates of PDDTE involving pediatric donors were very low and similar to rates from all donors, with resulting P/P transmissions occurring in only 0.1% of exposed recipients, but transmissions were associated with six deaths. Rates of P/P transmission to pediatric recipients from any donor (<0.1%) were also very low and similar to that of all recipients. Additional studies are needed to compare the pattern and outcome of donor‐derived disease transmission from and to pediatric and adult donor and recipients.     

Searches for matched and closely matched related and unrelated bone marrow donors undertaken in a single paediatric unit

Information regarding the likelihood of finding suitable marrow donors is limited. In order to determine this potential, all patients who received their primary care at a single paediatric institution over a 9 year period and in whom tissue typing studies were initiated are reviewed. Forty-five (31.3%) of 144 patients had a sibling who was human leucocyte antigen (HLA) identical. A further 16 (11.2%) patients had immediate or more distant relatives who were either HLA identical (2.7%) or matched for five of six HLA antigens (8.3%). The possibility that a parent was closely matched with the patient was suggestive from the typing of siblings alone in only half the cases. Unrelated HLA matched donors were identified in four (27%) of 17 bone marrow bank searches. Overall, a potential related donor was identified within the family for 42% of patients and this figure rose to 45% when successful marrow bank searches were included. It can be concluded that initial typing should include both the parents and siblings. If a suitable donor is not found then an extended family and/or bone marrow bank search will identify additional suitable donors in a significant number of families.     

Five decades with grandparent donors: The Norwegian strategy and experience

Living donors (LDs) are preferred over DDs for renal transplantation in children due to superior GS. Oslo University Hospital has never restricted living donation by upper age. The aim of this study was to investigate long‐term outcomes using grandparents (GPLD) compared to PLD. Retrospective nationwide review in the period 1970‐2017. First renal graft recipients using a GPLD were compared to PLD kidney recipients for long‐term renal function and GS. 278 children (≤18 years) received a first renal transplant: 27/251 recipients with a GPLD/PLD. GPLD (median 59 (42‐74) years) were significantly older than PLD (median 41 (23‐65) years, (P < .001). Median DRAD was 52 (38‐70) vs 28 (17‐48) years, respectively. GS from GPLD and PLD had a 1‐, 5‐, and 10‐year survival of 100%, 100%, and 90% vs 93%, 82%, and 72%, respectively (P = .6). In a multivariate Cox regression analysis adjusted for gender, donor age, recipient age, and year of transplant, this finding was similar (HR 0.98; 95% CI 0.34‐2.84, P = .97). Five‐year eGFR was 47.3 and 59.5 mL/min/1.73 m² in the GPLD and PLD groups (P = .028), respectively. In this nationwide retrospective analysis, GS for pediatric renal recipients using GPLD was comparable to PLD. Renal function assessed as eGFR was lower in the GPLD group. The GPLD group was significantly older than the PLD group, but overall this did not impact transplant outcome. Based on these findings, older age alone should not exclude grandparent donations.     

Use of organs from increased infectious risk deceased donors in pediatric kidney transplantation

Living donors are the main source of transplanted kidneys for children and young people in many countries, but there still remains a significant need for deceased donor kidney transplantation. Given the waiting times associated with deceased donor kidney transplantation and the morbidity or mortality that can occur in those on the waiting list, it is essential that the utilization of kidneys from deceased donors is optimized. The use of organs from deceased donors at increased risk of transmitting human immunodeficiency virus, hepatitis B virus, or hepatitis C virus is relatively common in adults, but far less so in children. The risks and benefits of the use of kidneys from increased infectious risk donors (IIRD) are discussed. The variation of definitions of IIRD between countries is explored as is the need for pediatric nephrologists and transplant surgeons to have an understanding of the prevalence of viral diseases within the country in which they work. The role of screening tests such as nucleic acid tests is examined, along with the concept of residual risk. Finally, considerations in acquiring informed consent in the use of kidneys from IIRDs in children and young people are discussed.     

Outcome after renal transplantation in children from native and immigrant families in Austria

Renal transplantation is the therapy of choice for children with end-stage renal disease (ESRD). Ethnicity affects the transplant survival rates substantially, but there has been no European academic evaluation of the effects of immigration on the pediatric renal transplantation outcome. The aim of this study was to compare the outcomes of renal transplantation between the children of immigrant families and the children of native families at the pediatric nephrology unit of the Medical University of Vienna, Austria. We conducted a retrospective study on all children who underwent renal transplantation at our center between January 1997 and June 2005. The patients were separated into two groups according to their immigration backgrounds. During the time frame of our study, 59 children underwent a total of 63 transplantations. Of these children, 42 were from native Austrian and 17 were from first-generation immigrant families. We analyzed the demographic data and outcome parameters for each of the 59 patients. We found no difference in patient and graft survival rates or long-term function between native and immigrant children. The two groups were also comparable in the rates of acute rejection episodes, 24-h blood pressure, and growth velocity. Living donor source had a positive influence on graft function (p=0.06), 24-h blood pressure (p=0.05), and growth velocity (p=0.02) only in the immigrant group. Our retrospective analysis shows no influence of the migration status on the patient or graft outcome, but we did find that immigrant children benefitted more than native children from living donation as opposed to deceased donation. To explain this fact, biological, heath-economical, psychosocial, and cultural background aspects must be investigated. Source of funding  Medical Scientific Fund of the Mayor of Vienna, project no. 2581.     

Bearbeitung und Transplantation hämatopoetischer Stammzellen

Background

New graft manipulation procedures make it possible to obtain highly purified hematopoietic stem cells from healthy donors.

Patients and Methods

A total of 116 children with leukemias, lymphomas, and nonmalignant diseases received purified (97%) peripheral stem cells from matched unrelated donors or mismatched related (haploidentical) donors.

Results

Acute and chronic GVHD were vastly minimized and a high overall rate of engraftment was achieved. Event-free survival at 5 years was 46% after haploidentical transplantation for children with ALL in remission who otherwise lacked a matched donor. Moreover, excellent results were observed in patients with nonmalignant diseases.

Conclusions

Graft manipulation results in well-characterized transplants with minimal risk of GVHD and makes a donor available for each patient by recruiting the parents. Thus, alternative donors should be strongly considered in all patients who need a stem cell transplantation but lack an identical donor.     

Diagnosis and management of childhood aplastic anaemia

Aplastic anaemia (AA) is a rare and heterogeneous disorder. AA results in pancytopenia and a hypocellular bone marrow in the absence of an abnormal infiltrate, major dysplasia or marrow fibrosis. In children, most cases are idiopathic and caused by T lymphocyte-mediated destruction of haemopoietic stem and progenitor cells (HSPC's). Inherited bone marrow failure syndromes (IBMFS) account for around 20% of cases and have to be excluded. This can be challenging but has specific implications for management. Haemopoietic stem cell transplantation (HSCT) is the only definitive curative treatment for AA. For patients less than 35 years old with severe aplastic anaemia (SAA), a matched sibling donor (MSD) haematopoietic stem cell transplant is the treatment of choice. For those lacking such a donor, immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and ciclosporin has historically been initial treatment. Improved outcomes following matched unrelated donors (MUD) transplantation has led to UK guidelines recommending upfront MUD HSCT in children and young adults where a suitable donor can be quickly identified. Recent advances in the treatment of patients with AA have shown that horse ATG with cyclosporine remains the current standard IST. The thrombopoietin receptor agonist eltrombopag has significant activity as a single agent and in combination with IST as initial treatment and in refractory patients. For patients with IBMFS, transplantation remains the only curative procedure.     

Chronic granulomatous disease 100% corrected by displacement bone marrow transplantation from a volunteer unrelated donor

A boy whose chronic granulomatous disease (CGD) manifested in infancy, and whose elder brother had died at 7 years of age, had phagocytes with complete lack of functional cytochrome B-245 and which could not be induced by interferon gamma to achieve adequate staphylococcal killing. He underwent an elective displacement bone marrow transplant from a volunteer unrelated donor at the age of 8 months. This has achieved 100% replacement of the CGD granulocytes by those of the normal volunteer and the boy has since had a normal childhood for 3 years. Six previous transplants for CGD are briefly reviewed and illustrate that the host abnormal marrow must be completely displaced using an adequate dose of busulphan to ensure 100% stable engraftment of the donor's marrow and that this is best done under elective conditions before septic foci and irreversible organ damage have occurred. Criteria need to be developed to identify early those patients likely to have severe morbidity.