Incidence of chronic renal injury in patients undergoing autologous stem cell transplant therapy.

BACKGROUND: Haemopoietic stem cell transplant (HSCT) is a well-established treatment option for many haematologic immunologic and oncologic diseases, allowing the safe administration of high-dose chemotherapy. Increased risk of acute renal injury is associated with HSCT; however, the risk of chronic kidney injury in autologous HSCT remains unclear. AIMS: This cohort study investigates the incidence of chronic renal injury and its predisposing factors in a single-centre population of 139 patients who underwent autologous HSCT. METHODS: Estimated glomerular filtration rate (eGFR) was measured at baseline and at 3, 6, 12 and 24 months following autologous stem cell reinfusion and used as a marker of renal dysfunction. RESULTS: A significant reduction in mean eGFR of patients was observed from baseline (80.62 ± 2.97 mL/min) to 24 months (71.54 ± 4.14 mL/min), independent of primary diagnosis (P = 0.0019). At baseline, 12% of the cohort had stage 3 or worse chronic renal injury and this increased to 38% by 24 months. By univariate analysis, age at baseline greater than the mean of 58 years and the occurrence of acute kidney injury during the peritransplant period emerged as predictive factors for the development of chronic kidney disease at 24 months. CONCLUSIONS: The current results indicate there is an increased incidence of chronic renal injury in patients who have undergone autologous peripheral blood haemopoietic stem cell transplantation therapy and this injury is potentiated by the autologous stem cell transplant procedure.

Pre infusion, post thaw CD34+ peripheral blood stem cell enumeration as a predictor of haematopoietic engraftment in autologous haematopoietic cell transplantation.

INTRODUCTION: By convention, peripheral blood stem cell products for autologous transplantation are evaluated for quality by CD34(+) cell dose at the time of harvesting. A CD34(+) cell dose in excess of 2.0 × 10(6)/kg of recipient body weight is considered adequate for haematopoietic engraftment. Viable CD34(+) cell numbers are enumerated in most laboratories using the ISHAGE single platform flow cytometric method which utilizes monoclonal antibodies to CD45, CD34 and 7 amino actinomycin D (7AAD) dye exclusion. METHODS: One hundred and six consecutive autologous transplantation procedures underwent viable CD34(+) cell enumeration at the time of harvesting and post thaw prior to re-infusion. Neutrophil and platelet engraftment and markers of haematopoietic support were analyzed. RESULTS: Mean pre-cryopreservation viable CD34(+) numbers were 4.882 × 10(6)/kg. Mean post thaw viable CD34(+) numbers were 3.234 × 10(6)/kg. Mean loss of viable CD34(+) cells with processing and cryo-preservation was 1.648 × 10(6)/kg (33%). For neutrophil engraftment, there was no significant difference between high (⩾ 3.0 × 10(6)/kg) and low (<1.5 × 10(6)/kg) post thaw viable CD34(+) cell counts (p=0.545). For platelet engraftment, there was however a significant difference observed between the high and low pre infusion viable CD34(+) groups (p<0.001). Additionally, significant differences were seen between the post thaw viable CD34(+) cell count and the associated length of hospital admission, days of use of G-CSF post transplantation, use of antibiotics in the post transplantation period and transfusion support in the post transplantation period. CONCLUSION: A significant loss of viable CD34(+) cells occurs during processing, cryopreservation and thawing. Low numbers of viable CD34(+) cells infused post thaw will still result in adequate neutrophil engraftment however may delay platelet engraftment. Low viable CD34(+) cell numbers have significant effects on admission duration and use of haematopoietic supportive measures with consequent effects on healthcare resources.

Gene doping: a review of performance-enhancing genetics.

Unethical athletes and their mentors have long arrogated scientific and medical advances to enhance athletic performance, thus gaining a dishonest competitive advantage. Building on advances in genetics, a new threat arises from athletes using gene therapy techniques in the same manner that some abused performance-enhancing drugs were used. Gene doping, as this is known, may produce spectacular physiologic alterations to dramatically enhance athletic abilities or physical appearance. Furthermore, gene doping may present pernicious problems for the regulatory agencies and investigatory laboratories that are entrusted to keep sporting events fair and ethical. Performance-enhanced genetics will likewise present unique challenges to physicians in many spheres of their practice.

Intermittent normobaric hypoxia does not alter performance or erythropoietic markers in highly trained distance runners.

This study was designed to test the hypothesis that intermittent normobaric hypoxia at rest is a sufficient stimulus to elicit changes in physiological measures associated with improved performance in highly trained distance runners. Fourteen national-class distance runners completed a 4-wk regimen (5:5-min hypoxia-to-normoxia ratio for 70 min, 5 times/wk) of intermittent normobaric hypoxia (Hyp) or placebo control (Norm) at rest. The experimental group was exposed to a graded decline in fraction of inspired O2: 0.12 (week 1), 0.11 (week 2), and 0.10 (weeks 3 and 4). The placebo control group was exposed to the same temporal regimen but breathed fraction of inspired O2 of 0.209 for the entire 4 wk. Subjects were matched for training history, gender, and baseline measures of maximal O2 uptake and 3,000-m time-trial performance in a randomized, balanced, double-blind design. These parameters, along with submaximal treadmill performance (economy, heart rate, lactate, and ventilation), were measured in duplicate before, as well as 1 and 3 wk after, the intervention. Hematologic indexes, including serum concentrations of erythropoietin and soluble transferrin receptor and reticulocyte parameters (flow cytometry), were measured twice before the intervention, on days 1, 5, 10, and 19 of the intervention, and 10 and 25 days after the intervention. There were no significant differences in maximal O2 uptake, 3,000-m time-trial performance, erythropoietin, soluble transferrin receptor, or reticulocyte parameters between groups at any time. Four weeks of a 5:5-min normobaric hypoxia exposure at rest for 70 min, 5 days/wk, is not a sufficient stimulus to elicit improved performance or change the normal level of erythropoiesis in highly trained runners.

Effect of altitude on second-generation blood tests to detect erythropoietin abuse by athletes.

BACKGROUND AND OBJECTIVES: ON- and OFF-model scores derived from blood parameters sensitive to erythropoiesis have been shown to be a useful tool to identify athletes who are currently injecting erythropoietin to enhance performance or those who have recently stopped doing so. We investigated changes in blood parameters and model scores during and after exposure to terrestrial and simulated altitudes. DESIGN AND METHODS: We retrospectively evaluated changes in hematologic data collected from 19 elite cyclists who lived and trained 2690 m above sea level for 26-31 days, from six elite Kenyan runners who lived 2100 m above sea level but descended to compete at sea level competitions, and from 39 well-trained subjects who resided at sea level but slept at a simulated altitude of 2650-3000 m for 20-23 days of either consecutive or intermittent nightly exposure. RESULTS: Upon ascent to a terrestrial altitude, ON- and OFF-model scores increased immediately, mainly because of an increase in hemoglobin concentration. Scores had not returned fully to baseline three weeks after return to sea level, because of the persistence of the raised hemoglobin concentration for the ON and OFF scores and a fall in reticulocyte percentage for OFF scores. Effects were smaller or negligible for simulated altitude. For Kenyan runners, ON- and OFF-model scores decreased within seven days of descent to sea level. INTERPRETATION AND CONCLUSIONS: Our results reinforce the notion that caution should be exercised when interpreting blood results from athletes who have recently been exposed to either terrestrial or simulated altitude, and appropriate allowance should be made for the effect of altitude on blood model scores.

The effect of common hematologic abnormalities on the ability of blood models to detect erythropoietin abuse by athletes.

BACKGROUND AND OBJECTIVES: Algorithms that combine scores from multiple blood parameters are demonstrably effective in highlighting recombinant human erythropoietin (rHuEPO) administration, and have been used to deter rHuEPO use by athletes. These models are sensitive to atypical levels of blood parameters encountered during altered states of red cell production. Because hematologic abnormalities can also result in unusual blood profiles, the aim of this study was to document the incidence and magnitude of such abnormalities in an elite athlete population. DESIGN AND METHODS: We screened blood samples obtained from 413 female and 739 male elite athletes from 12 countries for known hematologic abnormalities, and compared the algorithm scores for these athletes with those of their healthy counterparts. We also established the magnitude of blood parameters required for model scores to exceed cut-offs associated with rHuEPO use. RESULTS: We found that 0.7% of male and 2.4% of female athletes were iron deficient either with our without anemia. An additional 1.4% of males and 1.0% of females had hemoglobinopathies. On average these athletes' model scores were at or below the score of their healthy counterparts. The greatest influence on our models was hemoglobin concentration. Values of other parameters must exceed normal ranges by a substantial margin in order for model scores to approach levels associated with rHuEPO use. INTERPRETATION AND CONCLUSIONS: The hematologic disorders we encountered in elite athletes were not associated with model scores that exceeded the nominal cut-offs that we have previously recommended to delineate rHuEPO use. We did not find any abnormalities among elite endurance athletes that were associated with high model scores.

Second-generation blood tests to detect erythropoietin abuse by athletes.

BACKGROUND AND OBJECTIVES: We previously developed blood tests that were introduced at the Sydney 2000 Olympic Games to identify athletes injecting recombinant human erythropoietin (rHuEPO). The aim of this study was to re-analyse our existing database to develop models with heightened sensitivity, using wherever possible blood parameters measurable with appropriate standards of analytical performance. DESIGN AND METHODS: The principal database for this study was derived from a double-blind trial in which 57 recreational athletes were administered either rHuEPO or placebo. Standard discriminant analysis was used to derive two ON models (ON-hes and ON-he) and two OFF models (OFF-hr and OFF-hre) sensitive to accelerated and decelerated erythropoiesis respectively, utilising concentrations of hemoglobin (h), erythropoietin (e) and serum transferrin receptor (s), as well as percent reticulocytes (r). The ability of our models to detect rHuEPO administration was assessed by comparing model scores of subjects in the administration trial with the model scores of 1152 elite athletes from 12 countries. RESULTS: The ability of the new models to detect rHuEPO administration was generally higher than that of our previous models, particularly during phases when low doses of rHuEPO were used, and after injections had ceased. INTERPRETATION AND CONCLUSIONS. The increased stability of the new blood parameters facilitates transport of samples to central laboratories, and the heightened sensitivity of the new models makes them better than existing models for federations wishing to screen samples for urine testing and to identify and target suspect athletes for out-of-competition testing. However procedures should be incorporated that respect an elevated model score caused by genetic, health or environmental circumstances.

Development of reference ranges in elite athletes for markers of altered erythropoiesis.

BACKGROUND AND OBJECTIVES: Our previous research developed two statistical models that are useful indicators of current (ON-model) or recently discontinued (OFF-model) recombinant human erythropoietin (rHuEPO) use by athletes. The component variables of the ON-model are hematocrit (Hct), reticulocyte hematocrit (RetHct), serum erythropoietin (EPO), percent macrocytes (%Macro), and soluble transferrin receptor (sTfr), whilst the OFF-model uses only the first three variables. Genetics and training modalities of elite athletes may conceivably produce unusual values for blood parameters related to erythropoiesis. The aims of this study were to develop reference ranges in elite athletes for key hematologic parameters as well as ON- and OFF-models scores, and to evaluate the effect of ethnicity, gender, residence at moderate altitude (approximately 2000 m) and within-individual variation on the variables and model scores. DESIGN AND METHODS: Over a period of three weeks, 413 female and 739 male elite athletes from 12 countries visited laboratories to provide three blood samples for analysis of blood parameters sensitive to erythropoiesis. For each parameter and for the ON- and OFF-model scores, we used mixed modeling to establish the range within which we could be 95% certain that the value for a randomly chosen athlete would fall, taking into account various random effects (variation within and between subjects and laboratories) and fixed effects (means for different levels of ethnicity, age, sport, altitude of residency). We performed similar analyses for changes in the ON- and OFF-model scores between the three visits. RESULTS: Most fixed effects were accompanied by clear-cut, small to moderate differences in several parameters. However, residency at moderate altitude was accompanied by a much higher hematocrit than residency nearer sea level, with the mean (and 95% confidence limits) for the difference being 2.3 (0.9 to 3.7) and 1.8 (0.1 to 3.5) units for males and females, respectively. Males at altitude also demonstrated a moderately higher ON-model score. Otherwise the influence of these effects was small for ON-, OFF- and changes in model scores. INTERPRETATION AND CONCLUSIONS: Assessment of an athlete's blood parameters and ON- and OFF-model scores may need adjustment for training modalities and other characteristics of the subject. Changes in model scores (together with monitoring of urine samples for the presence of rHuEPO) provide a promising approach to detection of rHuEPO abuse, because they are less sensitive to subject characteristics and less variable than raw model scores.

Effects of prolonged low doses of recombinant human erythropoietin during submaximal and maximal exercise.

The aim of this study was to characterise the effect of prolonged low doses of recombinant erythropoietin (r-HuEPO) on the responses to submaximal and maximal exercise. Volunteer recreational athletes ( n=21) were divided into three groups: r-HuEPO+intravenous iron (EPO+IV, n=7), r-HuEPO+oral iron (EPO+OR, n=9) and placebo ( n=5). During the 12 week study, r-HuEPO or saline injections were given three times a week for the first 8 weeks and for the final 4 weeks the subjects were monitored but no injections were administered. The r-HuEPO doses were 50 IU x kg(-1) body mass for 3 weeks and 20 IU x kg(-1) body mass for the next 5 weeks. An exercise test comprising three submaximal intensities and then increments to elicit maximal aerobic power (VO2max ) was conducted during weeks 0, 4, 8 and 12. During week 0, the mean intensity of the submaximal stages was 60%, 72% and 81%. Blood taken at rest was analysed twice a week for haematocrit (Hct). The relative increases in at weeks 4, 8 and 12 were 7.7%, 9.7% and 4.5%, respectively, for the EPO+IV group; 6.0%, 4.7% and 3.1% for the EPO+OR group; and -0.5%, -0.1% and -1.0% for the placebo group, where the improvements at week 12 for the EPO+IV and EPO+OR groups remained significantly above week 0 values. The Hct was significantly elevated by 0.06 and 0.07 units at week 3 in the EPO+IV and EPO+OR groups, respectively, and was stable during the 5 weeks of low-dose r-HuEPO. After 8 weeks of r-HuEPO use, plasma lactate concentration tended to be lower at exercise intensities ranging from 60% to 100%. This study confirmed the ability of low doses of r-HuEPO to maintain Hct and at elevated levels.

Un nuevo método que utiliza marcadores de eritropoyesis alterada para la detección de abuso de eritropoyetina recombinante humana en deportistas / A novel method utilizing markers of altered erythropoiesis for the detection of recombinant human erythropoietin abuse in athletes

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