The Living Donor Collective: A Scientific Registry for Living Donors.

In the setting of an overall decline in living organ donation and new questions about long-term safety, a better understanding of outcomes after living donation has become imperative. Adequate information on outcomes important to donors may take many years to ascertain and may be evident only by comparing large numbers of donors with suitable controls. Previous studies have been unable to fully answer critical questions, primarily due to lack of appropriate controls, inadequate sample size, and/or follow-up duration that is too short to allow detection of important risks attributable to donation. The Organ Procurement and Transplantation Network does not follow donors long term and has no prospective control group with which to compare postdonation outcomes. There is a need to establish a national living donor registry and to prospectively follow donors over their lifetimes. In addition, there is a need to better understand the reasons many potential donors who volunteer to donate do not donate and whether the reasons are justified. Therefore, the US Health Resources and Services Administration asked the Scientific Registry of Transplant Recipients to establish a national registry to address these important questions. Here, we discuss the efforts, challenges, and opportunities inherent in establishing the Living Donor Collective.

Protecting the Kidney in Liver Transplant Recipients: Practice-Based Recommendations From the American Society of Transplantation Liver and Intestine Community of Practice.

Both acute and chronic kidney disease are common after liver transplantation and result in significant morbidity and mortality. The introduction of the Model for End-stage Liver Disease score has directly correlated with an increased prevalence of perioperative renal dysfunction and the number of simultaneous liver-kidney transplantations performed. Kidney dysfunction in this population is typically multifactorial and related to preexisting conditions, pretransplantation renal injury, perioperative events, and posttransplantation nephrotoxic immunosuppressive therapies. The management of kidney disease after liver transplantation is challenging, as by the time the serum creatinine level is significantly elevated, few interventions affect the course of progression. Also, immunological factors such as antibody-mediated kidney rejection have become of greater interest given the rising liver-kidney transplant population. Therefore, this review, assembled by experts in the field and endorsed by the American Society of Transplantation Liver and Intestine Community of Practice, provides a critical assessment of measures of renal function and interventions aimed at preserving renal function early and late after liver and simultaneous liver-kidney transplantation. Key points and practice-based recommendations for the prevention and management of kidney injury in this population are provided to offer guidance for clinicians and identify gaps in knowledge for future investigations.

De novo sirolimus and reduced-dose tacrolimus versus standard-dose tacrolimus after liver transplantation: the 2000-2003 phase II prospective randomized trial.

We studied whether the use of sirolimus with reduced-dose tacrolimus, as compared to standard-dose tacrolimus, after liver transplantation is safe, tolerated and efficacious. In an international multicenter, open-label, active-controlled randomized trial (2000-2003), adult primary liver transplant recipients (n=222) were randomly assigned immediately after transplantation to conventional-dose tacrolimus (trough: 7-15 ng/mL) or sirolimus (loading dose: 15 mg, initial dose: 5 mg titrated to a trough of 4-11 ng/mL) and reduced-dose tacrolimus (trough: 3-7 ng/mL). The study was terminated after 21 months due to imbalance in adverse events. The 24-month cumulative incidence of graft loss (26.4% vs. 12.5%, p=0.009) and patient death (20% vs. 8%, p=0.010) was higher in subjects receiving sirolimus. A numerically higher rate of hepatic artery thrombosis/portal vein thrombosis was observed in the sirolimus arm (8% vs. 3%, p=0.065). The incidence of sepsis was higher in the sirolimus arm (20.4% vs. 7.2%, p=0.006). Rates of acute cellular rejection were similar between the two groups. Early use of sirolimus using a loading dose followed by maintenance doses and reduced-dose tacrolimus in de novo liver transplant recipients is associated with higher rates of graft loss, death and sepsis when compared to the use of conventional-dose tacrolimus alone.

Daclizumab induction therapy in liver transplant recipients with renal insufficiency.

BACKGROUND: The role of interleukin 2 (IL-2) receptor antibodies to avoid the nephrotoxic effects of calcineurin inhibitors in the early post-liver transplant (LT) period is not well defined. AIM: To examine the use of daclizumab induction in LT recipients with renal insufficiency. METHODS: Between 2002 and 2005, 62 patients (median pre-LT creatinine 2.4 mg/dL, IQR 1.9-3.7) received daclizumab induction with tacrolimus being administered when serum creatinine was <2.0 mg/dL. A concurrent comparison group (n = 221, 2002-2005) received tacrolimus-based immunosuppression without daclizumab (median pre-LT creatinine 1.1 mg/dL, IQR 0.9-1.4). A second historical comparison group (n = 103, 1995-2005) not receiving daclizumab was matched to the daclizumab patients by pre-LT serum creatinine (2.2 mg/dL, IQR 1.8-3.1). All patients received mycophenolate mofetil and steroids. RESULTS: Serum creatinine improved in the daclizumab group (-1.0 mg/dL, IQR -2.2 to -0.4) and worsened in the concurrent comparison group (+0.2 mg/dL, IQR 0-0.5) from pre-LT to 4 months. However, there was no difference when daclizumab group was compared with the historical comparison group matched on pre-LT creatinine (median change: -0.8 mg/dL vs. -0.7 mg/dL). Daclizumab induction was not associated with improvement in renal function at 4 months (P = 0.34) after adjusting for pre-LT creatinine, age, gender, hepatitis C status and simultaneous liver kidney transplantation. CONCLUSION: The incremental benefit offered by induction therapy with IL-2 receptor antibodies to preserve renal function is questionable.

Correlation between optical coherence tomography and glaucomatous optic nerve head damage in children.

AIM: To compare analysis of macular and nerve fibre layer thickness by optical coherence tomography (OCT) with optic nerve head (ONH) morphology based on stereophotography. DESIGN: Prospective observational case-control series. METHODS: Normal and glaucomatous eyes of children (age 4-17 years) were scanned using Stratus OCT (Carl Zeiss Meditec, Dublin, California, USA). Fast macular and retinal nerve fibre layer (RNFL) thickness map were performed on 372 eyes of 222 children. ONH stereophotographs were taken and evaluated by two masked observers using a grading system of 0 to 5 based on both cupping ratio and morphology. OCT3 analyses were compared across ONH grades for different areas around the macula and the peripapillary RNFL. RESULTS: Analysis included OCT values and ONH grading for 139 eyes of 139 children. There was a negative correlation between ONH grade and both macular thickness and RNFL thickness in all areas measured. There was a difference in the correlation identified for black versus white children. CONCLUSION: OCT measurements of RNFL and macular thickness declined with increasing grade of glaucomatous damage seen on stereophotographs in black and white children. Further study will help quantify the value of OCT in the diagnosis and management of paediatric glaucoma.

Large diurnal fluctuations in intraocular pressure are an independent risk factor in patients with glaucoma.

PURPOSE: To study the risk associated with diurnal intraocular pressure (IOP) variations in patients with open-angle glaucoma. PATIENTS AND METHODS: Sixty-four patients (105 eyes) from the practices of two glaucoma specialists successfully performed home tonometry with a self-tonometer five times a day for 5 days. All patients had open-angle glaucoma and documented IOP below 25 mm Hg over a mean follow-up period of 5 years. Baseline status and time to progression of visual field loss were identified from the clinical charts. The level and variability of diurnal IOP obtained using home tonometry were characterized. Risk of progression was analyzed using a nonparametric time-to-event model, incorporating methods for correlated outcomes. RESULTS: Although mean home IOP and baseline office IOP were similar (16.4 +/- 3.6 mm Hg and 17.6 +/- 3.2 mm Hg, respectively), the average IOP range over the 5 days of home tonometry was 10.0 +/- 2.9 mm Hg. Baseline office IOP had no predictive value (relative hazard, 0.98). The diurnal IOP range and the IOP range over multiple days were significant risk factors for progression, even after adjusting for office IOP, age, race, gender, and visual field damage at baseline (relative hazards [95% confidence intervals], 5.69 [1.86, 17.35] and 5.76 [2.21, 14.98]). Eighty-eight percent of patients in the upper twenty-fifth percentile of IOP and 57% of patients in the lower twenty-fifth percentile progressed within 8 years. CONCLUSIONS: In patients with glaucoma with office IOP in the normal range, large fluctuations in diurnal IOP are a significant risk factor, independent of parameters obtained in the office. Fluctuations in IOP may be important in managing patients with glaucoma. Development of methods to control fluctuations in IOP may be warranted.

Does primary intraocular lens implantation prevent "aphakic" glaucoma in children?

PURPOSE: Open-angle glaucoma may develop after surgery for congenital or developmental cataract with an incidence ranging from 3% to 41%. The pathogenesis of "aphakic" (open-angle) glaucoma remains unknown. Despite numerous reported clinical series (>1000 eyes), we are unaware of any reported case of open-angle glaucoma after primary intraocular lens (IOL) implantation for congenital or developmental cataract. We decided to test the hypothesis that primary posterior chamber IOL implantation might decrease the incidence of open-angle glaucoma in children. METHODS: Pseudophakic eyes were collected from surgeons who contributed data to a refractive study and who monitored intraocular pressure on a regular basis. IOL implantation was commonly performed in eyes with a corneal diameter >10 mm. Comparable primary data on aphakic eyes were included from 2 published studies on aphakic glaucoma, which included corneal diameters and the patient's age at surgery. Glaucoma-free survival estimates for each cohort were estimated. RESULTS: Only 1 case of glaucoma was found among 377 eyes with primary pseudophakia (mean age of patient, 5.1 +/- 4.7 years; mean follow-up, 3.9 +/- 2.7 years). There were 14 eyes (11.3%) with glaucoma among 124 aphakic eyes (mean age of patient, 2.7 +/- 2.6 years; mean follow-up time, 7.2 +/- 3.9 years). CONCLUSIONS: We report a decreased incidence of open-angle glaucoma among eyes rendered primarily pseudophakic compared with those that remained aphakic after cataract surgery. We propose 2 theories on the possible mechanism of reduction in the incidence of glaucoma in pseudophakic eyes.

Noninvasive mapping of the normal retinal thickness at the posterior pole.

OBJECTIVE: Objective and sensitive measurements of the retinal thickness at the posterior pole are useful to detect and delineate macular edema or retinal atrophy. The authors therefore developed an instrument, the Retinal Thickness Analyzer (RTA), to map the retinal thickness rapidly. The RTA was used to study the normal thickness at the posterior pole and to provide a pilot baseline. DESIGN: Cross-sectional study. METHODS: A green (540-nm) laser slit was focused on the retina via a scanning mirror placed at the conjugate plane of the pupil. The intersection between the laser slit and the retina was viewed at an angle and recorded by a video camera. Nine scans, each acquired in 200 to 400 msec, covered the central 20 degrees of the fundus. PARTICIPANTS: The posterior pole was mapped in 29 normal subjects 19 to 76 years of age (mean, 48 years). RESULTS: The thickness maps matched the posterior pole anatomy. Points with maximum thickness were located in the perifovea in a C-shaped manner extending from the disc to above and below the fovea. The local variation (standard deviation) in retinal thickness among the subjects was, on average, 15 microns. Age, gender, and race did not have a large effect (< 35 microns) on the values. CONCLUSIONS: Rapid scanning thickness analysis with the RTA provides a detailed map of the retinal thickness. The relatively narrow range of thickness values in normal subjects indicates that the method may provide a sensitive detection of pathologic thickening or thinning of the retina.

Optical cross-sectional imaging of the macula with the retinal thickness analyzer in X-linked retinoschisis.

OBJECTIVE: To assess the morphologic characteristics of the foveal abnormality in juvenile X-linked retinoschisis using the scanning retinal thickness analyzer (RTA). This characteristic foveal abnormality is present in 83% to 100% of patients with X-linked retinoschisis and has not been demonstrated histopathologically. METHODS: The RTA is a noncontact imaging device. The RTA scans an obliquely oriented slit laser beam across the macula to obtain a series of optical cross sections, which are digitized. PARTICIPANTS: The RTA was used to examine 7 eyes of 5 patients with X-linked retinoschisis. RESULTS: The RTA demonstrated foveal schisis in all eyes examined. In 2 eyes of 2 patients, a single schisis cavity, with an inner leaf in a dome-shaped configuration, was present. In 4 eyes of 3 patients, a single schisis cavity containing fine strands was present. Some of these strands partially, and others completely, bridged the cavity. In 1 eye of 1 patient, 2 separate schisis cavities with bridging strands were present in the fovea. CONCLUSIONS: Scanning RTA is a noninvasive imaging modality capable of producing optical cross sections that demonstrate the extent and structural details of the foveal schisis in X-linked retinoschisis. Scanning RTA seems to be effective in the detection, characterization, and quantification of foveal schisis.

Quantitative detection of glaucomatous damage at the posterior pole by retinal thickness mapping. A pilot study.

OBJECTIVE: The posterior pole ganglion cell bodies form a substantial fraction of the retinal thickness, prompting the authors to study the feasibility of detecting, by scanning retinal thickness analysis, retinal changes at the posterior pole due to glaucomatous damage. STUDY DESIGN: Nonconsecutive case series. PARTICIPANTS: One or both eyes of patients with chronic open-angle glaucoma who presented with either a superoinferior asymmetry in visual fields or a localized field loss or a nerve fiber layer defect visible on photography were recruited. Twenty-nine eyes of 18 patients were studied. INTERVENTIONS: A laser slit was projected on the retina and scanned, in 400 msec, across a 2- x 2-mm area of the fundus, yielding optical cross-sections that were digitally recorded. Nine such scans covered the central 20 degrees of the fundus. The optical cross-sections were analyzed by an operator-free algorithm to yield a three-or two-dimensional color map. The asymmetry (difference) between the visual sensitivity of the upper and lower hemifields was compared with the asymmetry in retinal thickness deviation from normal. RESULTS: Large losses (up to 34%) in retinal thickness were detected at the posterior pole of patients with glaucoma due to the loss of ganglion cells and nerve fibers. A statistically significant correlation was found between the asymmetry in visual sensitivity loss and the asymmetry in deviation from normal thickness (r = 0.72; P < 0.0005). CONCLUSIONS: Mapping of the retinal thickness may provide a sensitive method for the detection and monitoring of early glaucomatous tissue loss in the posterior pole, which is unique due to the combination of (1) the direct measurement of neuroretinal loss in the central field of vision; (2) the mapping capability; and (3) the rapid image acquisition.

Serial optical sectioning of macular holes at different stages of development.

OBJECTIVE: This study aimed to examine the characteristics of intraretinal changes associated with macular holes and epiretinal membranes by scanning retinal thickness analysis. STUDY DESIGN: The study design was a nonconsecutive case series. PATIENTS: Fifty-six eyes of patients who had either a suspected or clinically diagnosed macular hole or epiretinal membrane were recruited. INTERVENTIONS: A commercial prototype of the scanning retinal thickness analyzer (RTA) was used. It projected a laser slit beam onto the retina and scanned it, in 200 or 400 msec, across a 2- x 2-mm area, yielding multiple optical cross sections that were recorded digitally. RESULTS: Epiretinal membranes were detected, and sites of attachment could be identified. Full-thickness holes corresponded to intraretinal cavities in which the inner retinal surface was broken, usually at the center. The majority of eyes with full-thickness macular holes showed increased retinal thickness surrounding the hole. The so-called "cuff of subretinal fluid," however, often was not present by retinal thickness analysis, despite clinical diagnosis to the contrary, even though retinal thickness analysis is capable of detecting such fluid. In 20 (42%) of 47 eyes diagnosed or suspected of having macular holes, scanning retinal thickness analysis showed findings different from those reported by retinal specialists. CONCLUSIONS: Examination of macular holes with the scanning RTA provides useful information in the diagnosis of macular holes in addition to that obtained through conventional techniques. The findings support the idea that many macular holes develop in association with intraretinal cystic changes. The precise chronology of the events remains to be determined.

Application of rapid scanning retinal thickness analysis in retinal diseases.

PURPOSE: The authors have further developed their method of retinal thickness analysis to rapidly generate multiple optical cross sections of the retina and provide thickness maps at the posterior pole. The potential use of this method was evaluated in a number of macular disorders. METHODS: A commercial prototype of the scanning retinal thickness analyzer was used to examine patients with a variety of macular diseases. A laser slit beam was projected on the retina and scanned across a 2- X 2-mm retinal area in 200 to 400 msec. The images of the intersection of the laser slit beam with the retina were recorded digitally and used for visualization of disease. Nine scans were combined, and an operator-free algorithm generated a three-dimensional thickness map at the posterior pole. RESULTS: Cysts could be visualized in macular edema associated with diabetes mellitus and with retinal vein occlusion. The retinal thickness map quantitated the location, extent, and height of the edema. In serous detachment, the extent and the height of the retinal pigment epithelial elevation could be documented. In cases of suspected macular holes and pseudoholes, the diagnosis was considered more reliable than with conventional biomicroscopy. The extent of epiretinal membranes, the sites of adherence, and associated intraretinal cystic changes were identified. In glaucoma, the anatomic course of localized loss of neuronal retinal tissue could be traced. CONCLUSIONS: Scanning retinal thickness analysis provided multiple optical cross sections of the retina and yielded information useful in the diagnosis and monitoring of macular diseases. The three-dimensional thickness map provided quantitative information that may be useful for clinical management.

Feasibility of laser-targeted photoocclusion of the choriocapillary layer in rats.

PURPOSE: A new method, laser-targeted photoocclusion, was developed to occlude choroidal neovascularization while minimizing damage to the overlying retina. The ability to occlude normal choriocapillary layer in rats was evaluated as a first test of the feasibility of treating choroidal neovascularization with this method. METHOD: A photosensitive agent, aluminum phthalocyanine tetrasulfonate, encapsulated in heat-sensitive liposomes, was administered intravenously along with carboxyfluorescein liposomes. A low-power argon laser (retinal power density of 5.7 W/cm2) locally released a photosensitizer bolus, monitored by the simultaneous release of carboxyfluorescein. A diode laser (operating at 675 nm with a retinal power density of 0.27 W/cm2) activated the photosensitizer with its release. RESULTS: Vessels in the choriocapillary layer were occluded at day 3 after laser treatment and remained unchanged during the 30-day follow-up. Larger choroidal vessels and retinal capillaries remained perfused. Control experiments excluded possible effects of heat or activation of free photosensitizer. Pilot histologic studies showed no damage to the retinal pigment epithelium. CONCLUSIONS: Laser-targeted photoocclusion caused selective occlusion of normal choriocapillaries while sparing overlying retinal pigment epithelium and retinal vessels. The method has potential as a treatment of choroidal neovascularization that may minimize iatrogenic loss of vision.

A new method for rapid mapping of the retinal thickness at the posterior pole.

PURPOSE: An objective, quantitative, and sensitive method to map retinal thickness is needed to diagnose more effectively the conditions causing alterations in thickness, such as macular edema and neuroretinal atrophy. METHODS: An instrument, the retinal thickness analyzer, was developed into a rapid scanning instrument, capable of covering macular areas of 2 x 2 mm in 200 or 400 msec and generating a detailed map of the retinal thickness. The performance was assessed in vitro and in five normal subjects who were scanned on three separate visits. RESULTS: Optimal depth precision was 5 to 10 microns, and the optimal depth resolution was 50 microns. Reproducibility was +/- 12 microns on the same day, +/- 13 microns for single maps obtained in multiple visits, and +/- 10 microns for three averaged maps per visit obtained in multiple visits. CONCLUSIONS: This new method to analyze retinal thickness provides four unique features: multiple optical cross-sectioning of the retina, mapping of retinal thickness, high reproducibility, and short acquisition time. These capabilities promise to improve the diagnosis and management of common diseases such as macular edema and glaucoma.

Selective visualization of choroidal neovascular membranes.

PURPOSE: Laser-targeted angiography has unique advantages over conventional angiography of the fundus. Its efficacy in visualizing choroidal neovascular membranes was tested in a rat model and compared to that of fluorescein angiography. METHOD: Laser-targeted angiography was performed in rats with choroidal neovascularization (CNV) by injecting heat-sensitive carboxyfluorescein liposomes intravenously, locally releasing a bolus of dye in the choroid with a weak laser pulse, and recording advancement of the bolus on a video camera. Conventional fluorescein angiography also was performed. RESULTS: Laser-targeted angiography revealed CNV as an abnormal pattern of brightly fluorescent vessels. The flow pattern of the bolus and histology, performed in some cases, confirmed the choroidal nature of the vessels. The angiographic visualization was not dependent on dye leakage through the vessels or staining of their walls. Laser-targeted angiography also provided visualization of new vessels that could not be diagnosed by fluorescein angiography. It demonstrated that blood flow was typically more sluggish in CNV than in normal choriocapillaris. Fluorescein angiography failed to demonstrate flow dynamics in all cases of CNV. CONCLUSIONS: This study, in an animal model of CNV, shows that laser-targeted angiography demonstrates CNV and its flow dynamics in a manner not provided by conventional fluorescein angiography. It holds clinical promise as a method to delineate CNV considered difficult or impossible to detect by fluorescein angiography. The method also may permit selective photocoagulation of feeding vessels in the choroid, thereby limiting damage to the overlying retina.

Management of bleb leaks after glaucoma filtering surgery. Use of autologous fibrin tissue glue as an alternative.

PURPOSE: To study the nature of bleb leaks after contemporary glaucoma filtering surgery as well as to evaluate various treatment modalities, including autologous fibrin tissue glue (AFTG) prepared in a modified manner. METHODS: Patients who presented to a Glaucoma Service during a 1-year period with a postoperative bleb leak were studied. Evaluation of various treatment modalities, including AFTG, was performed. RESULTS: Thirty-five episodes of bleb leaks were encountered in 25 eyes of 22 patients in a 1-year period. There was no statistically significant association between late or early leaks and the age or the race of the patient, previous eye surgery, or the use of antimetabolites at the time of filtering surgery. Eleven (31.4%) of the leaks were refractory to nonsurgical treatment modalities, 8 or them being of the late type. Successful healing of the leaks was obtained in 9 of the 12 episodes in which AFTG was used. However, there were no statistically significant differences between AFTG and the other treatment modalities. CONCLUSION: Bleb leaks are a common complication of contemporary glaucoma filtering surgery. Various nonsurgical and surgical modalities can be used in the treatment. In early as well as late bleb leaks, AFTG offers an alternative nonsurgical treatment and is at least as efficacious and may, in some ways, be superior to other nonsurgical modalities of treatment.

Noninvasive visualization of blood flow in the choriocapillaris of the rat.

PURPOSE: The rat has been used to generate models of various eye diseases. However, methods to study the choriocapillaris noninvasively have been inadequate in this species. Laser-targeted angiography was applied to generate local, repetitive angiograms of the choriocapillaris in the rat and to assess the similarity between the choriocapillaris of the rat and that of the subhuman primate. METHODS: Carboxyfluorescein was encapsulated in heat-sensitive liposomes and injected intravenously in rats. The liposome contents were then released locally in the choroid by the application of a short, noncoagulating heat pulse provided by an argon laser. Videoangiograms of the downstream spread of the bolus of dye were generated with excitation illumination provided by another output from the argon laser. RESULTS: Laser-targeted angiography demonstrated that the bolus of dye perfused the choriocapillaris. Clusters of choriocapillaris lobules were observed and appeared similar to those described in the primate. Dynamic filling and emptying patterns also were similar to those of the primate. Lobules were filled by a central arteriole and drained by a venous annulus. CONCLUSIONS: This study demonstrates the feasibility of noninvasively studying the choriocapillaris of the living rat using the technique of laser-targeted angiography. It demonstrates as well the similarity between the rat and the primate choriocapillaris, thus indicating that the rat is an acceptable and convenient model for the study of physiological and pathologic changes in the choroidal vasculature.