Seth J. Karp

The Medical Evaluation of Living Kidney Donors: A Survey of US Transplant Centers

The use of living donors for kidney transplantation in the United States is common, and long‐term studies have demonstrated the safety of donation by young, healthy individuals. However, transplant programs have little data to guide them in deciding which donors are unacceptable, and which characteristics are associated with kidney disease or poor psychosocial outcomes after donation. To document current practices in evaluating potential donors, we surveyed all US kidney transplant programs. Compared to a survey 12 years ago, medical criteria for donation are more inclusive in several areas. All responding programs now accept living unrelated donors. Most programs no longer have an upper age limit to be eligible. Programs are now more likely to accept donors with treated hypertension, or a history of kidney stones, provided that certain additional criteria are met. In contrast, medical criteria for donation are more restrictive in other areas, such as younger donor age and low creatinine clearance. Overall, significant variability remains among transplant programs in the criteria used to evaluate donors. These findings highlight the need for more data on long‐term outcomes in various types of donors with potential morbidities related to donation.

Evaluating living kidney donors: relationship types, psychosocial criteria, and consent processes at US transplant programs.

We conducted a survey of 132 US kidney transplant programs to examine how they evaluate and select potential living kidney donors, focusing on donor‐recipient relationships, psychosocial criteria, and consent processes. There is heterogeneity in donor‐recipient relationships that are considered acceptable, although most programs (70%) will not consider publicly solicited donors. Most programs (75%) require a psychosocial evaluation for all potential living donors. Most programs agree that knowledge of financial reward (90%), active substance abuse (86%), and active mental health problems (76%) are absolute contraindications to donation. However, there is greater variability in how other psychosocial issues are considered in the selection process. Consent processes are highly variable across programs: donor and recipient consent for the donor evaluation is presumed in 57% and 76% of programs, respectively. The use of 13 different informed consent elements varied from 65% (alternative donation procedures) to 86% (description of evaluation, surgery and recuperative period) of programs. Forty‐three percent use a ‘cooling off’ period. Findings demonstrate high variability in current practice regarding acceptable donor‐recipient relationships, psychosocial criteria, and consent processes. Whether greater consensus should be reached on these donor evaluation practices, especially in the context of more expansive use of living donor kidney transplantation, is discussed.

Restoration of Liver Mass after Injury Requires Proliferative and Not Embryonic Transcriptional Patterns

Normal adult liver is uniquely capable of renewal and repair after injury. Whether this response represents simple hyperplasia of various liver elements or requires recapitulation of the genetic program of the developing liver is not known. To study these possibilities, we examined transcriptional programs of adult liver after partial hepatectomy and contrasted these with developing embryonic liver. Principal component analysis demonstrated that the time series of gene expression during liver regeneration does not segregate according to developmental transcription patterns. Gene ontology analysis revealed that liver restoration after hepatectomy and liver development differ dramatically with regard to transcription factors and chromatin structure modification. In contrast, the tissues are similar with regard to proliferation-associated genes. Consistent with these findings, real-time polymerase chain reaction showed transcription factors known to be important in liver development are not induced during liver regeneration. These three lines of evidence suggest that at a transcriptional level restoration of liver mass after injury is best described as hepatocyte hyperplasia and not true regeneration. We speculate this novel pattern of gene expression may underlie the unique capacity of the liver to repair itself after injury.

Donor postextubation hypotension and age correlate with outcome after donation after cardiac death transplantation.

Background. Compared with standard donors, kidneys recovered from donors after cardiac death (DCD) exhibit higher rates of delayed graft function (DGF), and DCD livers demonstrate higher rates of biliary ischemia, graft loss, and worse patient survival. Current practice limits the use of these organs based on time from donor extubation to asystole, but data to support this is incomplete. We hypothesized that donor postextubation parameters, including duration and severity of hemodynamic instability or hypoxia might be a better predictor of subsequent graft function. Methods. We performed a retrospective examination of the New England Organ Bank DCD database, concentrating on donor factors including vital signs after withdrawal of support. Results. Prolonged, severe hypotension in the postextubation period was a better predictor of subsequent organ function that time from extubation to asystole. For DCD kidneys, this manifested as a trend toward increased DGF. For DCD livers, this manifested as increased rates of poor outcomes. Maximizing the predictive value of this test in the liver cohort suggested that greater than 15 min between the time when the donor systolic blood pressure drops below 50 mm Hg and flush correlates with increased rates of diffuse biliary ischemia, graft loss, or death. Donor age also correlated with worse outcome. Conclusions. Time between profound instability and cold perfusion is a better predictor of outcome than time from extubation to asystole. If validated, this information could be used to predict DGF after DCD renal transplant and improve outcomes after DCD liver transplant.

Excellent outcomes after transplantation of deceased donor kidneys with high terminal creatinine and mild pathologic lesions.

Background. Outcomes after kidney transplantation using deceased donors with high terminal creatinine are not well described but potentially represent an underutilized source of renal allografts. Utility of renal biopsy of these kidneys is similarly not well established. Methods. To better understand the posttransplant function of kidneys from donors with high terminal creatinine, we reviewed our database of almost 500 cadaveric kidney transplants. We compared the 65 nonexpanded criteria donors with a final donor creatinine ≥2.0 mg/dl (range 2.0–4.9 mg/dl) with kidneys procured from donors with terminal creatinine of <1.5. Biopsy results were correlated with graft function. Results. Kidneys from deceased donors with high terminal creatinine performed as well as kidneys from donors with a normal terminal creatinine with respect to primary non-function, acute rejection, 6-year graft and patient survival, and function over the first 48 months. High creatinine kidneys with moderate or severe lesions on biopsy demonstrated poorer function at 6 months and 1 year as compared to those with mild or no histological lesions. Conclusions. Under select conditions, kidneys from donors with high terminal creatinine can be used safely with excellent results.

New Serum Markers of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC), one of the most common cancers worldwide, usually develops in a liver already suffering from chronic damages, often cirrhosis. There has been marked progress in the treatment of HCC. However, effective treatments are limited to patients with less advanced HCC. The detection of HCC at an early stage is still a prerequisite for improved prognosis. To address this problem, a variety of screening modalities are used, including measurement of alpha-fetoprotein (AFP) and ultrasonography (US) at regular intervals in high-risk populations. Unfortunately, poor sensitivity and specificity of AFP and the operator-dependency of US limit the value of either test to diagnose early-stage lesions. Other tests, including Lens culinaris agglutinin-reactive AFP and des-gamma carboxyprothrombin (DCP), are currently being evaluated and may be superior to current tests. Recent developments in gene-expressing microarrays and proteomics promise even more potential diagnostic options. The strict application of the Early Detection Research Network methodology will aid in the assessment of their diagnostic utility, and provide an objective basis for the assessment of their clinical utility.

Practices and Barriers in Long-term Living Kidney Donor Follow-up: A Survey of U.s. Transplant Centers

Background. Many have called for more comprehensive follow-up of living kidney donors, both for the donor’s benefit and to establish a high-quality database of donor outcomes. United Network for Organ Sharing currently requires transplant centers to report donor follow-up information at several time points after donation, but little is known about how frequently this information is obtained, or which barriers exist to compliance with United Network for Organ Sharing requirements. Methods. To assess practices and barriers in providing follow-up care to living donors, we sent a questionnaire to all program directors at U.S. transplant centers. Results. Few transplant centers are currently seeing donors for long-term follow-up. Many centers recommend that donor follow-up care be provided by primary care physicians, but follow-up information is rarely received from primary care physicians. The main barriers to collecting more complete information are donor inconvenience, costs, and lack of reimbursement to the transplant center for providing follow-up care. Conclusions. Significant changes are required to improve long-term donor follow-up by U.S. transplant centers.

Photodynamic therapy inactivates extracellular matrix–basic fibroblast growth factor: Insights to its effect on the vascular wall

PURPOSE Photodynamic therapy (PDT), the light activation of photosensitizer dyes for the production of oxygen and other free radical moieties without the generation of heat, has been shown to inhibit the development of experimentally induced intimal hyperplasia. The host response to PDT, a form of vascular injury that results in complete vascular wall cell eradication, is devoid of inflammation and proliferation and promotes favorable vascular wall healing. These effects do not result in intimal hyperplasia and are suggestive of PDT-induced changes in the extracellular matrix (ECM). As a model to better understand the biologic consequences of PDT on the vascular wall matrix proteins, the effect of PDT was studied on the powerful matrix-resident mitogen basic fibroblast factor (bFGF) in vitro. METHODS PDT (5 to 200 J/cm2, 100 mW/cm2, 675 nm) was used with the photosensitizer chloroaluminum sulfonated phthalocyanine (5 micrograms/ml) to inactivate bFGF in vitro while 100 J/cm2 of irradiation was administered 24 hours after 5 mg/ml of the photosensitizer was used in vivo. PDT was used on bFGF in solution and on endothelial cell-derived ECM. Enzyme-linked immunosorbent assay was used to quantitate bFGF in solution after PDT treatment or after extraction from the ECM by collagenase and heparin. Functional activity of matrix-associated bFGF was assessed by smooth muscle cell mitogenesis by 3H-thymidine incorporation. To demonstrate the in vivo relevance of these observations, immunohistochemical analysis of PDT-treated rat carotid arteries was undertaken. RESULTS PDT eliminated detectable levels of bFGF in solution. PDT of ECM significantly reduced matrix-bound bFGF (1.0 +/- 0.6 vs 27.5 +/- 1.3 pg/ml; p < 0.0001). This reduction in bFGF after PDT of the ECM was associated with a decrease in vascular smooth muscle cell mitogenesis (52.4% +/- 4.6%; p < 0.0001) when plated on PDT-treated matrix compared with nontreated matrix. Quantitative replenishment of exogenous bFGF to PDT-treated matrix restored proliferation to baseline levels. PDT of rat carotid arteries demonstrated a loss of bFGF staining compared with control nontreated arteries. CONCLUSIONS PDT inactivation of matrix-resident bFGF and possibly other bioactive molecules can provide a mechanism by which PDT suppresses smooth muscle cell proliferation in the vessel wall. This free radical-mediated alteration of matrix may contribute to favorable vascular healing when PDT is used for the inhibition of injury-induced intimal hyperplasia.

Clinical implications of advances in the basic science of liver repair and regeneration.

Recent advances in our understanding of the basic mechanisms that control liver regeneration and repair will produce the next generation of therapies for human liver disease. Insights gained from large‐scale genetic analysis are producing a new framework within which to plan interventions. Identification of specific molecules that drive regeneration will increase the options for live‐donor liver transplantation, and help treat patients with small‐for‐size syndrome or large tumors who would otherwise have inadequate residual mass after resection. In a complementary fashion, breakthroughs in the ability to manipulate various cell types to adopt the hepatocyte or cholangiocyte phenotype promise to revolutionize therapy for acute liver failure and metabolic liver disease. Finally, elucidating the complex interactions of liver cells with each other and various matrix components during the response to injury is essential for fabricating a liver replacement device. This focused review will discuss how a variety of important scientific advances are likely to impact the treatment of specific types of liver disease.

Differential modulation of vascular endothelial and smooth muscle cell function by photodynamic therapy of extracellular matrix: Novel insights into radical-mediated prevention of intimal hyperplasia

PURPOSE Photodynamic therapy (PDT) has been demonstrated to inhibit experimental intimal hyperplasia and to lead to expedient reendothelialization but negligible repopulation of the vessel media. The mechanism that underlies the differential ingrowth of cells into PDT-treated vessel segments is not understood. Because the extracellular matrix (ECM) is known to modulate specific cell functions, this study was designed to determine whether PDT of isolated ECM affects the function of endothelial cells (ECs) and smooth muscle cells (SMCs). METHODS PDT of bovine aortic EC-ECM was performed with chloroaluminum sulfonated phthalocyanine and 675-nm laser light. Control specimens included untreated ECM, ECM-free plates, and ECM exposed to either light or photosensitizer only. Cell function was characterized by attachment, proliferation, and migration of ECs or SMCs that were plated onto identically treated matrixes. RESULTS SMC attachment (86% +/- 0.4% vs 95% +/- 0.4%), proliferation (46% +/- 0.5% vs 100% +/- 1.4%), and migration (40% +/- 1.0% vs 100% +/- 0.9%) were significantly inhibited after PDT of ECM when compared with untreated ECM (all p < 0.001). In contrast, PDT of ECM significantly enhanced EC proliferation (129% +/- 6.2% vs 100% +/- 6.2%; p < 0.03) and migration (118% +/- 2% vs 100% +/- 0.8; p < 0.01), but did not affect attachment. CONCLUSIONS This report establishes PDT-induced changes in the ECM with a result of inhibition of SMCs and stimulation of EC functions. It provides insight into how PDT-treated arteries can develop favorable EC repopulation without SMC-derived intimal hyperplasia. These findings may help provide a better understanding of the interactions between cells and their immediate environment in vascular remodeling.