The Incremental Cost of Incompatible Living Donor Kidney Transplantation: A National Cohort Analysis.

Incompatible living donor kidney transplantation (ILDKT) has been established as an effective option for end-stage renal disease patients with willing but HLA-incompatible living donors, reducing mortality and improving quality of life. Depending on antibody titer, ILDKT can require highly resource-intensive procedures, including intravenous immunoglobulin, plasma exchange, and/or cell-depleting antibody treatment, as well as protocol biopsies and donor-specific antibody testing. This study sought to compare the cost and Medicare reimbursement, exclusive of organ acquisition payment, for ILDKT (n = 926) with varying antibody titers to matched compatible transplants (n = 2762) performed between 2002 and 2011. Data were assembled from a national cohort study of ILDKT and a unique data set linking hospital cost accounting data and Medicare claims. ILDKT was more expensive than matched compatible transplantation, ranging from 20% higher adjusted costs for positive on Luminex assay but negative flow cytometric crossmatch, 26% higher for positive flow cytometric crossmatch but negative cytotoxic crossmatch, and 39% higher for positive cytotoxic crossmatch (p < 0.0001 for all). ILDKT was associated with longer median length of stay (12.9 vs. 7.8 days), higher Medicare payments ($91 330 vs. $63 782 p < 0.0001), and greater outlier payments. In conclusion, ILDKT increases the cost of and payments for kidney transplantation.

Quantifying the risk of incompatible kidney transplantation: a multicenter study.

Incompatible live donor kidney transplantation (ILDKT) offers a survival advantage over dialysis to patients with anti-HLA donor-specific antibody (DSA). Program-specific reports (PSRs) fail to account for ILDKT, placing this practice at regulatory risk. We collected DSA data, categorized as positive Luminex, negative flow crossmatch (PLNF) (n = 185), positive flow, negative cytotoxic crossmatch (PFNC) (n = 536) or positive cytotoxic crossmatch (PCC) (n = 304), from 22 centers. We tested associations between DSA, graft loss and mortality after adjusting for PSR model factors, using 9669 compatible patients as a comparison. PLNF patients had similar graft loss; however, PFNC (adjusted hazard ratio [aHR] = 1.64, 95% confidence interval [CI]: 1.15-2.23, p = 0.007) and PCC (aHR = 5.01, 95% CI: 3.71-6.77, p < 0.001) were associated with increased graft loss in the first year. PLNF patients had similar mortality; however, PFNC (aHR = 2.04; 95% CI: 1.28-3.26; p = 0.003) and PCC (aHR = 4.59; 95% CI: 2.98-7.07; p < 0.001) were associated with increased mortality. We simulated Centers for Medicare & Medicaid Services flagging to examine ILDKT's effect on the risk of being flagged. Compared to equal-quality centers performing no ILDKT, centers performing 5%, 10% or 20% PFNC had a 1.19-, 1.33- and 1.73-fold higher odds of being flagged. Centers performing 5%, 10% or 20% PCC had a 2.22-, 4.09- and 10.72-fold higher odds. Failure to account for ILDKT's increased risk places centers providing this life-saving treatment in jeopardy of regulatory intervention.

A novel organ donor facility: a decade of experience with liver donors.

Transplant surgeons have historically traveled to donor hospitals, performing complex, time-sensitive procedures with unfamiliar personnel. This often involves air travel, significant delays, and frequently occurs overnight.In 2001, we established the nation's first organ recovery center. The goal was to increase efficiency,reduce costs and reduce surgeon travel. Liver donors and recipients, donor costs, surgeon hours and travel time, from April 1,2001 through December 31,2011 were analyzed. Nine hundred and fifteen liver transplants performed at our center were analyzed based on procurement location (living donors and donation after cardiac death donors were excluded). In year 1, 36% (9/25) of donor procurements occurred at the organ procurement organization (OPO) facility, rising to 93%(56/60) in the last year of analysis. Travel time was reduced from 8 to 2.7 h (p<0.0001), with a reduction of surgeon fly outs by 93% (14/15) in 2011. Liver organ donor charges generated by the donor were reduced by37% overall for donors recovered at the OPO facility versus acute care hospital. Organs recovered in this novel facility resulted in significantly reduced surgeon hours, air travel and cost. This practice has major implications for cost containment and OPO national policy and could become the standard of care.

Effect of donor body mass index on the outcome of donation after cardiac death kidneys: how big is too big?

INTRODUCTION: Morbid obesity (MO) has become an epidemic in the United Sates and is associated with adverse effects on health. The purpose of this study was to examine the effects of MO on the short-term outcomes of kidneys transplanted from donation after cardiac death (DCD) donors. PATIENTS AND METHODS: Using a prospectively collected database, we reviewed 467 kidney transplantations performed at a single center between January 2008 and June 2011 to identify 67 recipients who received transplants from 40 DCD donors. The outcomes of 14 MO DCD donor kidneys were compared with 53 non-MO DCD grafts. MO was defined as a body mass index ≥ 35. Mean patient follow-up was 16 months. RESULTS: The MO and non-MO DCD donor groups were similar with respect to donor and recipient age, gender, race, cause of death and renal disease, time from withdrawal of life support to organ perfusion, mean human leukocyte antigen (HLA) mismatch, and overall recipient survival. Organs from MO DCD donors also had comparable rates of delayed graft function (21.4% vs 20.0%; P = not significant [NS]). At 1 year post-transplantation, a small but statistically insignificant difference was observed in the graft survival rates of MO and non-MO donors (87% vs. 96%; P = NS). One MO kidney had primary nonfunction. CONCLUSIONS: These data demonstrate that kidneys procured from MO DCD donors have equivalent short-term outcomes compared with non-MO grafts and should continue to be used. Further investigation is needed to examine the effect of MO on long-term renal allograft survival.

Immune responses to collagen-IV and fibronectin in renal transplant recipients with transplant glomerulopathy.

Antibodies (Abs) to donor HLA (donor-specific antibodies [DSA]) have been associated with transplant glomerulopathy (TG) following kidney transplantation (KTx). Immune responses to tissue-restricted self-antigens (self-Ags) have been proposed to play a role in chronic rejection. We determined whether KTx with TG have immune responses to self-Ags, Collagen-IV (Col-IV) and fibronectin (FN). DSA were determined by solid phase assay, Abs against Col-IV and FN by enzyme-linked immunosorbent assay and CD4+ T cells secreting interferon gamma (IFN-γ), IL-17 or IL-10 by ELISPOT. Development of Abs to self-Ags following KTx increased the risk for TG with an odds ratio of 22 (p-value = 0.001). Abs to self-Ags were IgG and IgM isotypes. Pretransplant Abs to self-Ags increased the risk of TG (22% vs. 10%, p < 0.05). Abs to self-Ags were identified frequently in KTx with DSA. TG patients demonstrated increased Col-IV and FN specific CD4+ T cells secreting IFN-γ and IL-17 with reduction in IL-10. We conclude that development of Abs to self-Ags is a risk factor and having both DSA and Abs to self-Ags increases the risk for TG. The increased frequency of self-Ag-specific IFN-γ and IL-17 cells with reduction in IL-10 demonstrate tolerance breakdown to self-Ags which we propose play a role in the pathogenesis of TG.

Investigations of kinetic interactions between lipid emulsions, hydroxyethyl starch or dextran and organophosphorus compounds.

CONTEXT: Numerous studies demonstrated a limited efficacy of clinically used oximes in case of poisoning by various organophosphorus compounds. A broad spectrum oxime antidote covering all organophosphorus nerve agents and pesticides is still missing and effective (bio-)scavengers have not yet been marketed. OBJECTIVE: The interactions of the available and clinically approved hydroxyethyl starch, dextran and lipid emulsions with organophosphorus nerve agents and pesticides were investigated in order to provide an in vitro base for the evaluation of these compounds in human organophosphorus poisoning. MATERIALS AND METHODS: The degradation kinetics of organophosphorus compounds by the glucose derivatives and lipid emulsions were investigated with an acetylcholinesterase inhibition assay. RESULTS: The incubation of organophosphorus compounds with TRIS-Ca(2+) buffer resulted in a time-dependent degradation of the nerve agents with half-lives of 42 min for cyclosarin, 49 min for sarin, 99 min for tabun, 107 min for soman 19 h for malaoxon and 54 h for VX. In contrast, incubation with all tested compounds resulted in a stabilisation of the organophosphorus compounds. DISCUSSION: Our results suggest that binding of lipophilic organophosphorus compounds could result in a reduced spontaneous and enzyme-induced degradation of the toxic compounds. CONCLUSION: High dose lipid emulsions and glucose derivatives stabilised organophosphorus compounds in vitro.

The impact of tax policies on living organ donations in the United States.

In an effort to increase living organ donation, fifteen states passed tax deductions and one a tax credit to help defray potential medical, lodging and wage loss costs between 2004 and 2008. To assess the impact of these policies on living donation rates, we used a differences-in-differences strategy that compares the pre- and postlegislation change in living donations in states that passed legislation against the same change in those states that did not. We found no statistically significant effect of these tax policies on donation rates. Furthermore, we found no evidence of any lagged effects, differential impacts by gender, race or donor relationship, or impacts on deceased donation. Possible hypotheses to explain our findings are: the cash value of the tax deduction may be too low to defray costs faced by donors, lack of public awareness about the existence of these policies, and that states that were proactive enough to pass tax policy laws may have already depleted donor pools with previous interventions.

ABO-incompatible organ transplantation.

Increases in the patients on the organ transplant wait list have far out paced the number of available organs. This has lead to longer time awaiting transplantation and thus increased morbidity and mortality associated with it. Making more organs available for transplantation remains critical, and hence, extended criteria donors and ABO-incompatible organs are being utilized. Recent reports on the use of conventional immunosuppressive regimens for ABO-incompatible grafts suggest outcomes can be obtained similar to those of ABO-compatible transplants. The delay in the development of natural antibodies to ABO antigens in infants provides an 'immunological window' that allows for successful ABO-incompatible transplants in this age group. This also allows for a unique mechanism long-term tolerance to the graft in infants. ABO incompatibility may no longer be a contraindication in case of kidney transplantation and paediatric heart transplantation. Increased utilization of ABO-incompatible grafts can alleviate the shortage for organs and decrease waitlist times and associated morbidity. In this review, we will discuss the current status of ABO-incompatible transplantation in adult and paediatric solid organ transplantation with attention on recent developments on understanding the mechanisms of graft acceptance in these ABO-incompatible organs.

The role of liver transplantation for hepatic adenomatosis in the pediatric population: case report and review of the literature.

Hepatic adenomas are benign lesions often found in young women during childbearing age. These tumors are often solitary but can also be multiple in which case this is referred to as hepatic adenomatosis (HA). HA is defined as having greater than or equal to ten adenomas within an otherwise normal liver. We present a case of a teenager with HA who underwent an orthotopic liver transplant for complications of her HA. To date there are only four reports of teenagers, without an underlying glycogen storage disease, who have undergone a liver transplant for HA. Liver transplantation within the pediatric population is an acceptable treatment for HA that are deemed unresectable.

Spatial characterization of T1 and T2 relaxation times and the water apparent diffusion coefficient in rabbit Achilles tendon subjected to tensile loading.

Tendons exhibit viscoelastic mechanical behavior under tensile loading. The elasticity arises from the collagen chains that form fibrils, while the viscous response arises from the interaction of the water with the solid matrix. Therefore, an understanding of the behavior of water in response to the application of a load is crucial to the understanding of the origin of the viscous response. Three-dimensional MRI mapping of rabbit Achilles tendons was performed at 2.0 T to characterize the response of T(1) and T(2) relaxation times and the apparent diffusion coefficient (ADC) of water to tensile loading. The ADC was measured in directions both parallel (ADC( parallel)) and perpendicular (ADC( perpendicular)) to the long axis of the tendon. At a short diffusion time (5.8 ms) MR parameter maps showed the existence of two regions, here termed "core" and "rim", that exhibited statistically significant differences in T(1), T(2), and ADC( perpendicular) under the baseline loading condition. MR parameter maps were also generated at a second loading condition of approximately 1 MPa. At a diffusion time of 5.8 ms, there was a statistically significant increase in the rim region for both ADC( perpendicular) (57.5%) and ADC( parallel) (20.5%) upon tensile loading. The changes in core ADC(( perpendicular), ( parallel)), as well as the relaxation parameters in both core and rim regions, were not statistically significant. The effect of diffusion time on the ADC(( perpendicular), ( parallel)) values was investigated by creating maps at three additional diffusion times (50.0, 125.0, 250.0 ms) using a diffusion-weighted, stimulated-echo (DW-STE) pulse sequence. At longer diffusion times, ADC(( perpendicular), ( parallel)) values increased rather than approaching a constant value. This observation was attributed to T(1) spin-editing during the DW-STE pulse sequence, which resulted in the loss of short-T(1) components (with correspondingly lower ADCs) at longer diffusion times (corroborating the results from earlier spectroscopic work). The T(1) spin-editing effect was observed both in the core and in the rim regions of the tendon and hence was not solely due to the redistribution of water from the core to the rim upon loading. A measure reflective of the regional change in proton density was noted to be consistent with tensile-load-induced water transport from the central to the peripheral tendon region.

Application of porous-media theory to the investigation of water ADC changes in rabbit Achilles tendon caused by tensile loading.

The water apparent diffusion coefficient (ADC) in rabbit Achilles tendon is anisotropic, diffusion-time dependent, and changes as a function of tensile load. Water ADC changes of tendon under mechanical load are thought to be due to the extrusion of water from the more restricted tendon core to a relatively unrestricted bulk phase at the periphery (rim) of the tendon. Tensile loading may influence water ADC values by changing the spatial separation of restricting barriers (e.g., increasing the tendon fibril packing density). To explore this issue, we have applied porous-media theory to the investigation of water ADC changes in rabbit Achilles tendon under two different mechanical loading conditions (a baseline condition with a minimal tensile stress and a second in which the tensile stress was approximately 1 MPa). Diffusion sensitivity was applied in directions parallel and perpendicular to the long axis of the tendon. The short diffusion-time behavior of the resulting time-dependent ADC curves was used to indirectly infer information regarding the average surface area to volume ratio of the space available for molecular diffusion. From these values, we estimated a 40% reduction in volume available for diffusion in the perpendicular direction after tensile loading, but only a 10% reduction in the parallel direction. These differences are consistent with the known geometry of the tendon microstructure and suggest an increase in fibril packing density upon loading. The long diffusion-time behavior of the time-dependent ADC curves was used to indirectly infer the tortuosity of the diffusion pathways through the interstitial space. The tortuosity in the direction perpendicular to the tendon long axis was approximately 2.5 times greater than that in the parallel direction. Stimulated-echo measurement of the ADC values at longer diffusion times resulted in T1 spin editing of water with shorter T1 values (and correspondingly lower ADC values). The resulting increase in water ADC with increasing diffusion time was attributed to multiple components arising from the (overlapping) distribution of T1 values in the core and rim regions of the tendon.

Measurement of the spatial redistribution of water in rabbit Achilles tendon in response to static tensile loading.

The redistribution of water in response to static tensile loading was investigated in rabbit Achilles tendons in vitro. The distribution of water was measured along a radially oriented line, using a one-dimensional proton-density map created from fits to diffusion-weighted magnetic resonance (MR) data. Water movements were measured during application of tensile loads of 5N (N=7) and 10N (N=6). Water distribution along the line was measured before loading and up to 42 min after load application. Static loading with either 5 or 10N loads caused a steady increase in proton density in the outside edge (rim) of the tendon. The 10N load lowered the proton density in the core of the tendon, but did so in a single step that was observed when the load was applied. The 5N load caused no change in proton density in the core region. The immediate redistribution from the core was statistically significant for the 10N load, but not the 5N load application. Statistically significant within-group proton-density increases were observed in the rim after 42 min postload for all tendons irrespective of load condition. The rate of proton-density postload increase at the rim region did not depend upon load. The rate for the 5N load case was 0.010 +/- 0.002 min(-1) and 0.007 +/- 0.002 min(-1) in the 10N case. Thus, while generally consistent with an extrusion model, the data show other features that argue for a more complex model.

Changes in ADC caused by tensile loading of rabbit achilles tendon: evidence for water transport.

Water diffusion measurements were performed on rabbit Achilles tendons during static tensile loading and tendons in an unloaded state. The apparent diffusion coefficient (ADC) was measured along two directions: parallel and perpendicular to the long axis of the tendon. Tendons were studied after being prepared in two ways: (a) after being stored frozen in phosphate-buffered saline (PBS) and (b) freshly isolated. Statistically significant directional anisotropy was observed in the ADC in all tendons. The ADC was significantly greater in the direction parallel to the long axis of the tendon than in the perpendicular direction. The anisotropy is attributed to the greater restrictions seen by the water molecules in the perpendicular direction and is consistent with the known geometry of the tendon. Storage in PBS caused tendons to swell. This increased the ADC measured along both directions and reduced the anisotropy. The existence of anisotropy in the ADC was not related to the orientation of the specimen in the magnet. The ADC increased along both directions following the application of a 5-N tensile load; the increase was greatest along the perpendicular axis of the tendon. In order to determine whether load-related changes in the ADC reflected changes in interfibrilar spacing, we used electron microscopy to measure load-related changes in fibril spacing. Load-related changes in fiber spacing could not account for the observed changes in the ADC. The increase in ADC caused by loading was attributed to the extrusion of tendon water into a bulk phase along the outside surface of the tendon. In PBS-stored samples, enough fluid was extruded that it could be visualized. The transient response of the ADC to a 5-N tensile load was also studied. The absolute ADC in both directions increased with loading and recovered to baseline upon unloading. The transient changes in ADC, for both loading and unloading, had a mean time constant of approximately 15 min. The magnitude of the load-induced transient ADC changes was comparable to that seen in the static-loading experiments.

Angiotensin II causes weight loss and decreases circulating insulin-like growth factor I in rats through a pressor-independent mechanism.

The renin-angiotensin system regulates normal cardiovascular homeostasis and is activated in certain forms of hypertension and in heart failure. Angiotensin II has multiple physiological effects and we have shown recently that its growth-promoting effects on vascular smooth muscle require autocrine activation of the IGF I receptor. To study the effect of angiotensin II on circulating IGF I, we infused rats with 500 ng/kg/min angiotensin II for up to 14 d. Angiotensin II markedly reduced plasma IGF I levels (56 and 41% decrease at 1 and 2 wk, respectively) and IGF binding protein-3 levels, and increased IGF binding protein-2 levels, a pattern suggestive of dietary restriction. Compared with sham, angiotensin II-infused hypertensive rats lost 18-26% of body weight by 1 wk, and pair-feeding experiments indicated that 74% of this loss was attributable to a reduction in food intake. The vasodilator hydralazine and the AT1 receptor antagonist losartan had comparable effects to reverse angiotensin II-induced hypertension, but only losartan blocked the changes in body weight and in circulating IGF I and its binding proteins produced by angiotensin II. Moreover, in Dahl rats that were hypertensive in response to a high-salt diet, none of these changes occurred. Thus, angiotensin II produces weight loss through a pressor-independent mechanism that includes a marked anorexigenic effect and an additional (likely metabolic) effect. These findings have profound implications for understanding the pathophysiology of conditions, such as congestive heart failure, in which the renin-angiotensin system is activated.

Salivary and plasma androstenedione and 17-hydroxyprogesterone levels in congenital adrenal hyperplasia.

Androstenedione (A-dione) and 17-hydroxyprogesterone (17-OHP) levels were measured in matched samples of saliva and of plasma collected from patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (eight patients) and 11-hydroxylase deficiency (one patient). Positive correlations were found between salivary and plasma values of either steroid with correlation coefficients of 0.968 for A-dione and 0.935 for 17-OHP. All five inadequately treated patients with 21-hydroxylase deficiency had greatly elevated plasma and salivary 17-OHP concentrations compared to values in age matched controls. In two of three well controlled patients plasma 17-OHP levels were less than 40 nmol/liter and salivary levels were less than 1.5 nmol/liter, the upper limits which have been formulated as a guideline for monitoring control in treated CAH patients. Patients in good control had A-dione levels in plasma (0.6-2.2 nmol/liter) and saliva (0.04-0.15 nmol/liter) which were both within the normal range for prepubertal children (0.14-2.40 nmol/liter and 0.02-0.25 nmol/liter respectively). Patients in poor control had A-dione levels in plasma of 5.2-25.4 nmol and in saliva of 0.50-2.21 nmol/liter. These values exceeded without exception the normal ranges for their respective ages. Salivary A-dione and 17-OHP determinations are a useful adjunct in the diagnosis and the monitoring of CAH patients since they can be obtained easily and nonstressfully.

Testosterone and delta 4-androstenedione in the saliva of patients with Klinefelter's syndrome.

This study compares salivary and total plasma levels of testosterone and androstenedione in healthy controls and chromatin positive patients with Klinefelter's syndrome. The mean plasma testosterone level in fifteen Klinefelter patients was significantly lower than in ten control subjects, but the mean androstenedione levels were similar. Saliva of the normal men and patients with Klinefelter's syndrome did not differ significantly in binding potency for testosterone or androstenedione. The mean salivary testosterone level in the Klinefelter patients was significantly lower than in the controls but again salivary androstenedione levels were similar. Although testosterone as well as androstenedione showed a fair correlation between the salivary and plasma concentrations, preliminary data suggested that salivary testosterone levels better characterize the clinical state of androgenicity than do plasma levels. When salivary testosterone and androstenedione were expressed as a percentage of total steroid levels in plasma, the ratios for both steroids were similar in Klinefelter patients and healthy controls and closely approximated to the reported percentages of free steroid levels in plasma. The absolute salivary testosterone concentrations also were almost identical to the reported free plasma hormone levels. Together the data provide indirect evidence that in Klinefelter patients testosterone and androstenedione binding in plasma and saliva does not differ from that in normal men, and measurement of salivary steroids, by reflecting their free hormone concentration in plasma, may be useful in evaluating endocrine function in both health and disease.