Evaluation of C1q Status and Titer of De Novo Donor-Specific Antibodies as Predictors of Allograft Survival.

De novo donor-specific antibodies (dnDSAs) that develop after renal transplantation are independent predictors of allograft loss. However, it is unknown if dnDSA C1q status or titer at the time of first detection can independently predict allograft loss. In a consecutive cohort of 508 renal transplant recipients, 70 developed dnDSAs. Histologic and clinical outcomes were correlated with the C1q assay or dnDSA titer. C1q positivity correlated with dnDSA titer (p < 0.01) and mean fluorescence intensity (p < 0.01) and was more common in class II versus class I dnDSAs (p < 0.01). C1q status correlated with tubulitis (p = 0.02) and C4d status (p = 0.03) in biopsies at the time of dnDSA development, but not T cell-mediated rejection (TCMR) or antibody-mediated rejection (ABMR). De novo DSA titer correlated with Banff g, i, t, ptc, C4d scores, TCMR (p < 0.01) and ABMR (p < 0.01). Post-dnDSA graft loss was observed more frequently in recipients with C1q-positve dnDSA (p < 0.01) or dnDSA titer ≥ 1:1024 (p ≤ 0.01). However, after adjustment for clinical phenotype and nonadherence in multivariate models, neither C1q status nor dnDSA titer were independently associated with allograft loss, questioning the utility of these assays at the time of dnDSA development.

Rates and determinants of progression to graft failure in kidney allograft recipients with de novo donor-specific antibody.

Understanding rates and determinants of clinical pathologic progression for recipients with de novo donor-specific antibody (dnDSA), especially subclinical dnDSA, may identify surrogate endpoints and inform clinical trial design. A consecutive cohort of 508 renal transplant recipients (n = 64 with dnDSA) was studied. Recipients (n = 388) without dnDSA or dysfunction had an eGFR decline of -0.65 mL/min/1.73 m(2) /year. In recipients with dnDSA, the rate eGFR decline was significantly increased prior to dnDSA onset (-2.89 vs. -0.65 mL/min/1.73 m(2) /year, p < 0.0001) and accelerated post-dnDSA (-3.63 vs. -2.89 mL/min/1.73 m(2) /year, p < 0.0001), suggesting that dnDSA is both a marker and contributor to ongoing alloimmunity. Time to 50% post-dnDSA graft loss was longer in recipients with subclinical versus a clinical dnDSA phenotype (8.3 vs. 3.3 years, p < 0.0001). Analysis of 1091 allograft biopsies found that dnDSA and time independently predicted chronic glomerulopathy (cg), but not interstitial fibrosis and tubular atrophy (IFTA). Early T cell-mediated rejection, nonadherence, and time were multivariate predictors of IFTA. Independent risk factors for post-dnDSA graft survival available prior to, or at the time of, dnDSA detection were delayed graft function, nonadherence, dnDSA mean fluorescence intensity sum score, tubulitis, and cg. Ultimately, dnDSA is part of a continuum of mixed alloimmune-mediated injury, which requires solutions targeting T and B cells.

Economic consequences incurred by living kidney donors: a Canadian multi-center prospective study.

Some living kidney donors incur economic consequences as a result of donation; however, these costs are poorly quantified. We developed a framework to comprehensively assess economic consequences from the donor perspective including out-of-pocket cost, lost wages and home productivity loss. We prospectively enrolled 100 living kidney donors from seven Canadian centers between 2004 and 2008 and collected and valued economic consequences ($CAD 2008) at 3 months and 1 year after donation. Almost all (96%) donors experienced economic consequences, with 94% reporting travel costs and 47% reporting lost pay. The average and median costs of lost pay were $2144 (SD 4167) and $0 (25th-75th percentile 0, 2794), respectively. For other expenses (travel, accommodation, medication and medical), mean and median costs were $1780 (SD 2504) and $821 (25th-75th percentile 242, 2271), respectively. From the donor perspective, mean cost was $3268 (SD 4704); one-third of donors incurred cost >$3000, and 15% >$8000. The majority of donors (83%) reported inability to perform usual household activities for an average duration of 33 days; 8% reported out-of-pocket costs for assistance with these activities. The economic impact of living kidney donation for some individuals is large. We advocate for programs to reimburse living donors for their legitimate costs.

Class II HLA epitope matching-A strategy to minimize de novo donor-specific antibody development and improve outcomes.

De novo donor-specific antibody (dnDSA) develops in 15-25% of renal transplant recipients within 5 years of transplantation and is associated with 40% lower graft survival at 10 years. HLA epitope matching is a novel strategy that may minimize dnDSA development. HLAMatchmaker software was used to characterize epitope mismatches at 395 potential HLA-DR/DQ/DP conformational epitopes for 286 donor-recipient pairs. Epitope specificities were assigned using single antigen HLA bead analysis and correlated with known monoclonal alloantibody epitope targets. Locus-specific epitope mismatches were more numerous in patients who developed HLA-DR dnDSA alone (21.4 vs. 13.2, p < 0.02) or HLA-DQ dnDSA alone (27.5 vs. 17.3, p < 0.001). An optimal threshold for epitope mismatches (10 for HLA-DR, 17 for HLA-DQ) was defined that was associated with minimal development of Class II dnDSA. Applying these thresholds, zero and 2.7% of patients developed dnDSA against HLA-DR and HLA-DQ, respectively, after a median of 6.9 years. Epitope specificity analysis revealed that 3 HLA-DR and 3 HLA-DQ epitopes were independent multivariate predictors of Class II dnDSA. HLA-DR and DQ epitope matching outperforms traditional low-resolution antigen-based matching and has the potential to minimize the risk of de novo Class II DSA development, thereby improving long-term graft outcome.

Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant.

The natural history for patients with de novo donor-specific antibodies (dnDSA) and the risk factors for its development have not been well defined. Furthermore, clinical and histologic correlation with serologic data is limited. We studied 315 consecutive renal transplants without pretransplant DSA, with a mean follow-up of 6.2 ± 2.9 years. Protocol (n = 215) and for cause (n = 163) biopsies were analyzed. Solid phase assays were used to screen for dnDSA posttransplant. A total of 47 out of 315 (15%) patients developed dnDSA at a mean of 4.6 ± 3.0 years posttransplant. Independent predictors of dnDSA were HLA-DRß1 MM > 0 (OR 5.66, p < 0.006); and nonadherence (OR 8.75, p < 0.001); with a strong trend toward clinical rejection episodes preceding dnDSA (OR 1.57 per rejection episode, p = 0.061). The median 10-year graft survival for those with dnDSA was lower than the No dnDSA group (57% vs. 96%, p < 0.0001). Pathology consistent with antibody-mediated injury can occur and progress in patients with dnDSA in the absence of graft dysfunction and furthermore, nonadherence and cellular rejection contribute to dnDSA development and progression to graft loss.

Access to living donor transplantation for Aboriginal recipients: a study of living donor presentation and exclusion.

Aboriginals experience high rates of end-stage renal disease (ESRD) and are less likely to receive a kidney transplant from a living donor. We hypothesized that higher rates of hypertension and diabetes in Aboriginal communities would result in fewer potential living donors coming forward and more exclusions for medical reasons. We performed a retrospective study to examine the frequency of potential donor presentation and the reasons for donor exclusion among Aboriginal and Caucasian wait-listed ESRD patients at our center. Three hundred and eighty-five wait-listed patients were studied, including 174 Aboriginals and 211 Caucasians. Time on the waiting list was similar between groups. A similar proportion of Aboriginals and Caucasians had at least one potential donor (40% vs. 46%), and the rate of donor exclusion for medical reasons was also similar (23% vs. 21%). Potential donors to Aboriginals were more likely to be excluded for non-medical reasons (50% vs. 30%; p < 0.0001), of which 96% were because of loss of contact. Waitlisted Aboriginal ESRD patients appear just as likely as Caucasians to have potential living donors initiate evaluation and have a similar rate of donor exclusion because of medical reasons. Further work is required to identify why donors to Aboriginals are more likely to withdraw from the evaluation process.

Experimental extraction of secure correlations from a noisy private state.

We report experimental generation of a noisy entangled four-photon state that exhibits a separation between the secure key contents and distillable entanglement, a hallmark feature of the recently established quantum theory of private states. The privacy analysis, based on the full tomographic reconstruction of the prepared state, is utilized in a proof-of-principle key generation. The inferiority of distillation-based strategies to extract the key is exposed by an implementation of an entanglement distillation protocol for the produced state.

Retinal nerve fiber thickness in inflammatory demyelinating diseases of childhood onset.

PURPOSE: To evaluate retinal nerve fiber layer thickness (RNFLT) using optical coherence tomography (OCT) in children with acquired demyelinating diseases. METHODS: This is a cross-sectional study of patients seen between 2006-2008 at the Pediatric MS Center of the Jacobs Neurological Institute. Consensus definitions for pediatric demyelinating disease were followed. All children received OCT testing and assessment of visual acuity (VA) using Snellen and low contrast letter acuity (LCLA) charts. RESULTS: Thirty-eight children diagnosed with acquired demyelinating disease, 15 healthy controls, and five children with other neurological disorders (OND) were included. Average RNFLT in healthy controls was 107 +/- 12 microm(n = 30) versus 108 +/- 5 microm (n = 10) in OND controls. In children with multiple sclerosis, average RNFLT +/- SD was 99 +/- 14 microm in unaffected (n = 24) versus 83 +/- 12 micromin eyes affected by optic neuritis ("affected eyes") (n = 10). Average RNFLT in children with acute disseminated encephalomyelitis and transverse myelitis was 102 +/- 15 microm in unaffected (n = 18) versus 67 +/- 17 microm in affected eyes (n = 6). In children with optic neuritis (ON), average RNFLT +/- SD was 97 +/- 13 microm in unaffected (n = 5) versus 89 +/- 12 microm in affected eyes (n = 9). Differences between children with demyelinating disease and controls and between ON and nonON eyes were statistically significant (P < 0.001). Bivariate correlations of RNFLT with LCLA (P = 0.002) and VA (P < 0.001) were significant. CONCLUSIONS: OCT may be a valuable tool for the assessment and monitoring of anterior optic pathway dysfunction in children with demyelinating diseases.

Health outcomes for living kidney donors with isolated medical abnormalities: a systematic review.

Individuals with isolated medical abnormalities (IMAs) are undergoing living donor nephrectomy more frequently. Knowledge of health risks for these living donors is important for donor selection, informed consent and follow-up. We systematically reviewed studies with > or = 3 living kidney donors with preexisting IMAs, including older age, obesity, hypertension, reduced glomerular filtration rate (GFR), proteinuria, microscopic hematuria and nephrolithiasis. We abstracted data on study and donor characteristics, perioperative outcomes, longer term renal and blood pressure outcomes and mortality and compared them to those of non-IMA donors. We found 22 studies on older donors (n = 987), 10 on obese donors (n = 484), 6 on hypertensive donors (n = 125), 4 on donors with nephrolithiasis (n = 32), 2 on donors with microscopic hematuria and one study each on donors with proteinuria or reduced GFR. Perioperative outcomes for donors with and without IMAs were similar. Few studies reported longer term (> or = 1 year) rates of hypertension, proteinuria or renal function. Studies were frequently retrospective and without a comparison group. Given the variability among studies and their methodological limitations, uncertainties remain regarding long-term medical outcomes for IMA donors. As transplant centers continue to cautiously screen and counsel potential IMA donors, rigorously conducted, longer term prospective cohort studies are needed.

Differences in tolerance for health risk to the living donor among potential donors, recipients, and transplant professionals.

In organ donation, the donor, recipient, and transplant team must all accept potential health risks to the donor and any uncertainties. To gauge these risks, we surveyed general altruism and risk-taking behaviors in 112 potential donors, 111 potential recipients, and 51 transplant professionals. Next, participants indicated their risk thresholds for long-term donor hypertension, cardiovascular disease, and kidney failure that would stop them from pursuing living donation and their willingness to proceed when risks were uncertain. The three groups had similar general altruism and risk-taking behaviors. Potential donors were significantly more willing to accept greater long-term donor risks than potential recipients and transplant professionals. Moreover, these potential donors were significantly more likely to agree that living donation was acceptable when long-term donor risks were uncertain. Potential kidney donors readily accept high long-term risks, whereas potential recipients were the most averse to donor risk. Our study shows that transplant professionals facilitate the best decisions by appreciating the willingness of their patients to accept donor health risks along with their own risk tolerance.

Kidney transplantation outcomes in Canadian aboriginals.

Aboriginal populations experience a very high rate of end-stage renal disease (ESRD); however, little is known about the outcomes of transplantation in this population. We performed a retrospective database review to determine the short- and long-term outcomes of kidney transplantation in Aboriginals. Adult Aboriginal (AB) and Caucasian (C) individuals receiving primary kidney transplants between 1969 and 2003 in Manitoba, Canada were examined. A total of 705 recipients were included (126 AB and 579 C). AB recipients were younger, had different etiologies of ESRD, longer cold-ischemic times for deceased donor transplants, and higher peak panel reactive antibody levels. At 1 year post-transplant, there was no difference in serum creatinine, acute rejection or graft survival between AB and C recipients. However, AB recipients experienced greater weight gains early post-transplant and were more likely to develop post-transplant diabetes mellitus. AB recipients exhibited inferior 10-year graft (AB 26% vs. C 47%, p < 0.01) and patient survival (AB 50% vs. 75%, p < 0.01). When graft survival was censored for death with a functioning graft, there was no difference between the two groups. Multivariate analysis revealed AB race to be an independent predictor of premature graft failure and patient death. In conclusion, kidney transplant outcomes have historically been inferior in the Manitoba population of Canadian Aboriginals.

Creating a new market niche: family caregiver training.

Home care agencies, recognizing the important part that the family caregiver plays in their new operating plans, are incorporating family caregivers in a way that allows everyone to benefit.

Posterior lumbar interbody fusion and cages.

The author of the paper presents an overview of posterior lumbar interbody fusion (PLIF), including a historical note, a global surgical strategy as well as specific indications for this procedure (discogenic low back pain, spondylosis, spondylolisthesis, recurrent disc herniation, failed chemonucleolysis, spinal stenosis). A short description of surgical technique can also be found in the paper. The author also emphasises the possible complications linked with this procedure and the need for experienced surgeons in order to decrease the number of postoperative complications. Finally the paper contains a short description of the most commonly used implants during surgical corrections of lumbar biomechanics.

Does subclinical rejection contribute to chronic rejection in renal transplant patients?

Renal allograft biopsies have traditionally been performed in the setting of acute graft dysfunction. However, several groups have performed graft biopsies at times of stable graft function, and more recently, after treatment of rejection episodes. Surprisingly, unequivocal histologic criteria for acute rejection have been demonstrated in a high proportion of these protocol biopsies. The Winnipeg Transplant Group has documented the high prevalence of clinically silent inflammatory infiltrates in early protocol biopsies, and demonstrated their inflammatory and cytotoxic potential by immunohistochemical and molecular biological techniques. Furthermore, in a randomized trial, our group has demonstrated that subclinical rejection, if untreated, is associated with the development of early chronic pathology and late graft dysfunction. In this overview, we will summarize the early data on subclinical allograft inflammation, present the experience of the Winnipeg Transplant Group, and discuss the possible implications of subclinical rejection on the development of chronic rejection.

A computer assisted orthopaedic surgical system for distal locking of intramedullary nails.

This paper presents a prototype system for computer assisted surgery, the purpose of which is to assist orthopaedic surgeons when performing distal locking of intramedullary nails. This system comprises three components, namely: an Intelligent Image Intensifier, a Trajectory Tactician and an Intelligent Trajectory Guide. The Intelligent Image Intensifier is an X-ray vision system that provides accurate X-ray images. Such images enable the Trajectory Tactician software to analyse the operation site and calculate the trajectory required for a screw to lock an intramedullary nail. This involves the capture of two X-ray images from which are extracted the projections of the nail's edge boundaries and its distal locking holes. Using an analytical mathematical model of the nail, the position and orientation of the nail is determined. The trajectory is then implemented by the surgeon using the Intelligent Trajectory Guide. Evaluation in the laboratory suggests that the system is capable of reliably inserting a locking screw into an intramedullary nail. The rapidity with which this computer assisted method achieves locking should benefit both patient and surgeon by reducing radiation dosage and the length of time required to lock a nail.

A follow-along study of postsecondary outcomes for graduates and dropouts with mild disabilities in a rural setting.

Eighty-six students with mild disabilities living in a rural area who had graduated (n = 52) or dropped out of (n = 34) high school were interviewed at two points in time (7 months apart) about their employment, residential status, and participation in postsecondary education and training programs. Information was also collected on students' high school experiences (educational, vocational, and work) and the reasons they dropped out of school. Of the students who had graduated (Caucasian = 26, black = 25, and other = 1), 31 were male and 21 were female. Of the students who had dropped out (Caucasian = 18, black = 15, and other = 1), 22 were male and 12 female. It was found that the majority of graduates and dropouts were employed full-time at both interviews, and held jobs that paid above minimum wage and provided employee benefits, as well. Nevertheless, by the time of the terminal interview, graduates had worked proportionally more time since high school than dropouts and had been employed in their current job more than twice as long. Neither group of former special education students was particularly active in pursuing postsecondary education or training programs. Finally, these former students had participated in a limited range of educational and vocational experiences during high school, both in terms of diploma tracks and vocational education programs. The implications of the findings for long-term employment and community adjustment are discussed.

The penetration of antibiotics into the normal intervertebral disc.

The role of antibiotics in the treatment of disc-space infection is controversial. This study assessed the tissue penetration of flucloxacillin and cephradine into the normal intervertebral disc after intravenous administration of a bolus dose of antibiotic. Twenty-five discs were removed from 12 adolescent patients having anterior spinal surgery to correct scoliosis; antibiotic had been administered between 30 minutes and four hours before operation. Despite high blood levels, no antibiotic could be detected by bioassay or by high-pressure liquid chromatography (h.p.l.c.) in any of the specimens from the nucleus pulposus or the annulus fibrosus.

Hinged knee replacement in revision arthroplasty.

Fifty-two Stanmore hinged knee replacements were used as revision arthroplasties for failed arthroplasties. The patients were followed for a mean of 44.7 months. On clinical examination, 23% had good, 48% fair, and 29% poor results. Worst results were achieved when revising bulkier or more constrained primary knee joints. Two patients exhibited radiologic evidence of loosening, but at the latest follow-up examination no patients had clinical evidence of loosening. There was an infection rate of 4%. In view of the poor results and the advent of a new generation of knee arthroplasty devices, hinged knee implants may have only a limited place in revision arthroplasty.

The results and morbidity of varus osteotomy for Perthes' disease.

The results of varus proximal femoral osteotomy in 55 hips in 52 patients were analyzed by Harrison's radiologic autoassessment method. Excluding operations upon Catterall Grade 1 hips, 75.6% were either therapeutic successes or unchanged; 24.4% were therapeutic failures. These results are compared with and shown to be similar to those of patients treated conservatively by the Birmingham splint. In ten children with Catterall Grade 1 disease, seven were unchanged but three were therapeutic failures. Improved end results occurred in hips with greater surgical varus than those in which the end result worsened, but the statistical significance was questionable. The bone remodelling in response to surgical varus was unpredictable, but the greater the surgical varus the less the correction of the neck shaft angle at follow-up evaluation. Chronologic age cannot be used to predict such bone remodelling as may be impaired by the disease process. An analysis of the incidence and significance of leg shortening, limping, and abductor lurch is presented and some observations made on trochanteric overgrowth and the effect of surgery on the rate of femoral head reconstitution. New attempts to achieve containment of the hip by high-femoral osteotomy may determine the effects of a combination of varus and selective rotation osteotomy using ultrasound scans to measure femoral torsion before operation.

Medullary femoral nailing of pathological fractures using the Derby nail--a preliminary report of 22 cases.

A new medullary femoral nail is reported. The device provides dynamic compression, producing rigid stabilization with resistance to rotational stresses. We present 22 cases of pathological fractures of the femur treated by the Derby nail. Rigid fixation was achieved with no sepsis, loosening or implant failure at the latest follow-up or death. The mean time spent in hospital was 20 days and patients took full weight, on average, by the 9th postoperative day.