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.

The independent living donor advocate: a guidance document from the American Society of Transplantation's Living Donor Community of Practice (AST LDCOP).

The independent living donor advocate (ILDA) serves a mandated and supportive role in the care of the living organ donor, yet qualifications and role requirements are not clearly defined. Guidance comes from Centers for Medicare and Medicaid Services (CMS) Conditions for Transplant Center Participation and interpretive guidelines, Organ Procurement and Transplantation Network (OPTN) Policy and CMS and OPTN site surveys, yet interpretation of regulations varies. Herein, the AST Living Donor Community of Practice (LDCOP) offers seven recommendations to clarify and optimize the ILDA role: (a) the ILDA must have a certain skill set rather than a specific profession, (b) the ILDA must be educated and demonstrate competence in core knowledge components, (c) the ILDA's primary role is to assess components of informed consent, (d) centers must develop a transparent system to define ILDA independence, (e) the ILDA should have a reporting structure outside the transplant center, (f) the ILDA's role should be integrated throughout the donor care continuum, (g) the ILDA role should include a narrow "veto power." We address controversies in ILDA implementation, and offer pathways to maximize benefits and minimize limitations of approaches that may each meet regulatory requirements but confer different practice benefits. We propose a research agenda to explore the impact of the ILDA.

Emotional well-being of living kidney donors: findings from the RELIVE Study.

Following kidney donation, short-term quality of life outcomes compare favorably to US normative data but long-term effects on mood are not known. In the Renal and Lung Living Donors Evaluation Study (RELIVE), records from donations performed 1963-2005 were reviewed for depression and antidepressant use predonation. Postdonation, in a cross-sectional cohort design 2010-2012, donors completed the Patient Health Questionnaire (PHQ-9) depression screening instrument, the Life Orientation Test-Revised, 36-Item Short Form Health Survey and donation experience questions. Of 6909 eligible donors, 3470 were contacted and 2455 participated (71%). The percent with depressive symptoms (8%; PHQ-9>10) was similar to National Health and Nutrition Examination Survey participants (7%, p=0.30). Predonation psychiatric disorders were more common in unrelated than related donors (p=0.05). Postdonation predictors of depressive symptoms included nonwhite race OR=2.00, p=0.020), younger age at donation (OR=1.33 per 10 years, p=0.002), longer recovery time from donation (OR=1.74, p=0.0009), greater financial burden (OR=1.32, p=0.013) and feeling morally obligated to donate (OR=1.23, p=0.003). While cross-sectional prevalence of depression is comparable to population normative data, some factors identifiable around time of donation, including longer recovery, financial stressors, younger age and moral obligation to donate may identify donors more likely to develop future depression, providing an opportunity for intervention.

Demographic, metabolic, and blood pressure characteristics of living kidney donors spanning five decades.

While cautious criteria for selection of living kidney donors are credited for favorable outcomes, recent practice changes may include acceptance of less than ideal donors. To characterize trends in donor acceptance, the Renal and Lung Living Donors Evaluation (RELIVE) Study evaluated 8,951 kidney donors who donated between 1963 and 2007 at three major U.S. transplant centers. Over the study interval, there was an increase in the percentage of donors >40 years old from 38% to 51%; donors >60 years varied between 1% and 4%. The proportion of donors with obesity increased from 8% to 26% and with glucose intolerance from 9% to 25%. The percentage of hypertensive donors was consistent (5-8%). Accepted donors ≥60 years old were more likely to have obesity, glucose intolerance, and/or hypertension compared to younger donors (p<0.0001). Our results demonstrate important trends in acceptance of older and more obese donors. The fraction of older donors accepted with glucose intolerance or hypertension remains small and for the majority includes mild elevations in glucose or blood pressure that were previously classified as within normal limits.

Health-related quality of life in kidney donors from the last five decades: results from the RELIVE study.

Live donation benefits recipients, but the long-term consequences for donors remain uncertain. Renal and Lung Living Donors Evaluation Study surveyed kidney donors (N = 2455; 61% women; mean age 58, aged 24-94; mean time from donation 17 years, range 5-48 years) using the Short Form-36 Health Survey (SF-36). The 95% confidence intervals for White and African-American donors included or exceeded SF-36 norms. Over 80% of donors reported average or above average health for their age and sex (p < 0.0001). Donors' age-sex adjusted physical component summary (PCS) scores declined by half a point each decade after donation (p = 0.0027); there was no decline in mental component summary (MCS) scores. White donors' PCS scores were three points higher (p = 0.0004) than non-Whites'; this difference remained constant over time. Nine percent of donors had impaired health (PCS or MCS score >1 SD below norm). Obesity, history of psychiatric difficulties and non-White race were risk factors for impaired physical health; history of psychiatric difficulties was a risk factor for impaired mental health. Education, older donation age and a first-degree relation to the recipient were protective factors. One percent reported that donation affected their health very negatively. Enhanced predonation evaluation and counseling may be warranted, along with ongoing monitoring for overweight donors.

Living donor age and kidney transplant outcomes.

We assessed the relationship between living donor (LD) age and kidney survival in 1063 adults transplanted between 1980 and 2007. Increasing LD age was associated with lower kidney function (GFR) before and after transplantation and loss of GFR beyond 1 year. Increasing LD age was also associated with low-moderate proteinuria posttransplant (151-1500 mg/day, p < 0.0001). By univariate analysis, reduced graft survival related to lower GFR at 1 year [HR = 0.925 (0.906-0.944), p < 0.0001], proteinuria [HR = 1.481 (1.333-1.646), p < 0.0001] and increasing LD age [HR = 1.271 (1.219-1.326), p = 0.001]. The impact of LD age on graft survival was noted particularly >4 years posttransplant and was modified by recipient age. Thus, compared to a kidney graft that was within 5 years of the recipient age, younger kidneys had a survival advantage [HR = 0.600 (0.380-0.949), p = 0.029] while older kidneys had a survival disadvantage [HR = 2.217 (1.507-3.261), p < 0.0001]. However, this effect was seen only in recipients <50 years old. By multivariate analysis, the relationship between LD age and graft survival was independent of GFR but related to proteinuria. In conclusion, LD age is an important determinant of long-term graft survival, particularly in younger recipients. Older kidneys with reduced survival are identifiable by the development of proteinuria posttransplant.

Role of steroid dose in hypertension early after liver transplantation with tacrolimus (FK506) and cyclosporine.

Transplant immunosuppression using either cyclosporine (CsA) or tacrolimus (FK506) leads to renal vasoconstriction and nephrotoxicity. Despite producing similar effects within the kidney and blood vessels, clinical hypertension occurs less frequently with tacrolimus during the first year after transplantation, compared with CsA. To examine the role of steroid dose in early posttransplant hypertension, we measured blood pressure and kidney function in liver transplant recipients treated with tacrolimus and either high-dose (TAC-HI-P, n = 19) or low-dose (TAC-LO-P,n = 20) prednisone, compared with CsA-treated recipients (n = 29) receiving prednisone doses similar to the TAC-HI-P group. At 1 month, hypertension occurred more often with CsA (72%) than with TAC-HI-P (42%, P < 0.05) or TAC-LO-P (30%, P < 0.05). By 4 months after transplantation, hypertension developed in nearly twice as many TAC-HI-P (63%) as TAC-LO-P patients (32%, P < 0.05), with no difference between TAC-HI-P and CsA (86%, NS). Daily prednisone dose at 1 month closely paralleled cumulative steroid dose in the first month in the TAC-HI-P and TAC-LO-P groups. Fourteen of 19 TAC-HI-P patients (74%) required bolus steroids for treatment of rejection within the first month, compared with 3/20 (15%) TAC-LO-P and 10/29 (34%) CsA recipients. Glomerular filtration rate fell from pretransplant levels at 1 month and 4 months to the same degree in CsA, TAC-HI-P, and TAC-LO-P patients. These results demonstrate a central role for steroid dose in the rate of onset of hypertension early after liver transplantation using tacrolimus immunosuppression. Both daily dose and cumulative dosage, including bolus treatment for rejection, may impact on the development of hypertension. Since prevalence rates rise to levels comparable to CsA by 24 months regardless of steroid dose, hypertension after liver transplant may be mediated by different mechanisms at different stages of the posttransplant course.

Hypertension in women: current understanding of gender differences.

High blood pressure is a major individual and public-health issue because of its wide prevalence and associated complications. More women than men have hypertension, but until recently, women have been relatively underrepresented in clinical trials. Gender differences in the physiology, genetics, and treatment benefit of hypertension have been noted in several studies that have included women. These findings have raised concerns about the generalizability of the results of previous investigations to women. The currently available information regarding gender differences and similarities and the results of hypertension treatment trials in women are reviewed herein. These studies suggest that, although gender differences exist, women benefit significantly when they receive therapy to normalize blood pressure.

Cyclosporine-induced hypertension after transplantation.

OBJECTIVE: To describe the features and mechanisms of posttransplantation hypertension and suggest appropriate management of the disorder. DESIGN: We review our own experience and reports from the literature on hypertension in cyclosporine A (CSA)-treated transplant recipients. RESULTS: Soon after immunosuppression with CSA and corticosteroids, hypertension develops in most patients who undergo transplantation. The blood pressure increases, which are usually moderate, occur universally because of increased peripheral vascular resistance. Disturbances in circadian patterns of blood pressure lead to loss of the normal nocturnal decline, a feature that magnifies hypertensive target effects. Changes in blood pressure sometimes are severe and associated with rapidly developing target injury, including intracranial hemorrhage, left ventricular hypertrophy, and microangiopathic hemolysis. The complex mechanisms that underlie this disorder include alterations in vascular reactivity that cause widespread vasoconstriction. Vascular effects in the kidney lead to reduced glomerular filtration and impaired sodium excretion. Many of these changes affect local regulation of vascular tone, including stimulation of endothelin and suppression of vasodilating prostaglandins. Effective therapy includes use of vasodilating agents, often calcium channel blocking drugs. Caution must be exercised to avoid interfering with the disposition of CSA or aggravating adverse effects relative to kidney and electrolyte homeostasis. CONCLUSION: Recognition and treatment of CSA-induced hypertension and vascular injury are important elements in managing the transplant recipient.

Loss of nocturnal blood pressure fall after liver transplantation during immunosuppressive therapy.

Hypertension, which develops after organ transplantation during immunosuppression with cyclosporine (CSA), is often associated with a loss of nocturnal decrease in blood pressure. Few data correlate circadian blood pressure patterns before transplant with those observed at fixed time points after transplant, or address the role of alternate immunosuppressive agents such as FK506. FK506 is unrelated structurally to CSA and less often leads to hypertension early after transplant. The present study compared nocturnal blood pressure patterns in patients with end-stage liver disease (ESLD) before transplant to those of transplant recipients receiving either FK506 (0.15 mg/kg/day) plus prednisone or CSA (2 to 3 mg/kg/day) plus prednisone and azathioprine after orthotopic liver transplantation. Overnight ambulatory blood pressure profiles were studied in 13 pretransplant ESLD patients and in 34 patients (FK506: n = 13; CSA: n = 21) treated with different steroid doses (24 +/- 11 mg/day FK506; 34 +/- 3 mg/day CSA), according to protocol, 4 weeks (range, 2 to 7 weeks) after liver transplant. Mean blood pressure and heart rate values from awake and nocturnal 5-h time blocks were compared to 13 normotensive control subjects. Patients with ESLD were normotensive and maintained a normal nocturnal blood pressure fall (125 +/- 3/74 +/- 2 mm Hg awake; 109 +/- 3/60 +/- 2 mm Hg nocturnal). Awake ambulatory blood pressures were higher in CSA patients than in FK506 patients (148 +/- 3/95 +/- 2 v 128 +/- 3/78 +/- 2 mm Hg, respectively; P < .01), despite reduced glomerular filtration rates in both transplant groups. Both immunosuppressive regimens led to a loss of nocturnal blood pressure fall, as compared to ESLD patients or normotensive controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypertension after liver transplantation: a predictive role for pretreatment hemodynamics and effects of isradipine on the systemic and renal circulations.

Hypertension developing after liver transplantation during immunosuppression with cyclosporine A reflects an unusual hemodynamic transition from peripheral vasodilation to systemic and renal vasoconstriction. Although dihydropyridine calcium channel blockers are often administered for their efficacy in promoting vasodilation, some liver transplant recipients report marked symptomatic intolerance to these agents. In the present study we examined systemic and renal responses to isradipine using systemic (thoracic bioimpedance) and renal hemodynamic measurements in 15 liver transplant recipients studied at the time of initial diagnosis of posttransplant hypertension and after 3 months of treatment. Circadian blood pressure patterns were examined by overnight ambulatory blood pressure monitoring before and during antihypertensive therapy. During isradipine administration, blood pressure decreased from 151 +/- 3/91 +/- 2 to 130 +/-3/81 +/- 2 mm Hg (P < .01) without change in renal blood flow (406 +/- 43 to 425 +/- 52 mL/min/1.73m2, P = NS) or renal vascular resistance index (25,674 +/-3312 to 20,520 +/- 2311 dynes x sec x cm(-5)/m2, P = NS). Pre-treatment differences in systemic vascular tone persisted during treatment and predicted the tendency for symptomatic tachycardia and flushing, predominantly in those with hyperdynamic circulations. Twice daily dosing of isradipine was associated with partial and significant restoration of the nocturnal decrease in blood pressure (systolic blood pressure decreased 5.5%, normal 13%), usually absent early after transplantation. Our results demonstrate the ability of hemodynamic measurements to predict the symptomatic response to antihypertensive therapy in the posttransplant setting.

Case-control study of galactorrhea and its relationship to the use of oral contraceptives.

A case-control study was performed to determine the relationship between galactorrhea and the use of oral contraceptives as well as other risk factors. The cases included all 109 Olmsted County residents who satisfied the diagnostic criteria for galactorrhea between 1970 and 1980. Control subjects were selected from a sampling frame of all medical registrations and matched to the cases by age, year, and residency. Pituitary adenomas were strongly associated with galactorrhea, as the relative risk was 23.2 (95% confidence interval 2.0 to 90.0). In galactorrhea cases without pituitary adenomas there was an association with oral contraceptives (ever use versus never use), as the relative risk was 2.3 (95% confidence interval 1.3 to 4.4). Among current users of oral contraceptives, the risk of galactorrhea was not increased, but there was a trend of diminishing risk with duration of use. The estimate of relative risk was 3.1 after discontinuation of oral contraceptive use and was highest for the first year after discontinuation (5.5), compared with a year or more after discontinuation (2.1). Thus, galactorrhea was associated with the cessation of oral contraceptives.

Cyclosporin-induced hypertension: incidence, pathogenesis and management.

Blood pressure increases soon after administration of immunosuppressive regimens using cyclosporin. Characteristic vascular changes lead to systemic and renal vasoconstriction. Changes in blood pressure are commonly associated with disturbed circadian regulation and may promote the rapid development of target organ injury, including intracranial haemorrhage, left ventricular hypertrophy and microangiopathic haemolysis. The mechanisms underlying this disorder are complex and include altered vascular endothelial function. Vasodilators such as prostacyclin and nitric oxide are suppressed, whereas vasoconstrictors, including endothelin, are increased. Changes in the kidney include vasoconstriction, reduced glomerular filtration and sodium retention. Effective therapy depends upon rigorous blood pressure control by administration of vasodilating agents, with attention to potential interactions with cyclosporin.

Renal artery stenosis and a functioning hilar paraganglioma: a rare cause of renovascular hypertension--a case report.

Surgically correctable causes of hypertension are uncommon. Simultaneous occurrence of 2 such causes in the same individual is extremely rare. The authors describe a 25-year-old woman with congenital erythrocytosis, renal artery stenosis, and a paraganglioma. The possible mechanisms of renal artery stenosis in the presence of a catecholamine-secreting tumor are discussed.

Glomerular volume and renal histology in obese and non-obese living kidney donors.

The link between obesity and renal disease is unclear, and there is no consensus as to whether obese individuals are at increased risk for kidney disease after living kidney donation if they otherwise meet acceptance criteria. We retrospectively studied time-zero (implantation) biopsies in 49 obese (body mass index (BMI) > or = 30 kg/m2) and 41 non-obese (BMI < 30 kg/m2) renal donors that met acceptance criteria. We found that our obese donor population had higher systolic blood pressure (P < 0.001 vs non-obese) and higher absolute iothalamate clearance (P = 0.001 vs non-obese) before donation. The obese donors had larger glomerular planar surface area compared to non-obese controls (P = 0.017), and this parameter correlated with patient weight and urinary microalbumin excretion. Detailed examination of the biopsies revealed that although most histologic findings were similar between groups, the obese donors had more tubular dilation (P = 0.01), but less tubular vacuolization (P = 0.02) than the non-obese controls. There was also a trend toward more arterial hyalinosis in the obese patients than controls (P = 0.08). From these data, our studies detected subtle differences in donor organs obtained from obese compared to non-obese individuals. Further studies should be carried out to quantify the long-term impact of these findings.

A hemodynamic approach to resistant hypertension.

Resistant hypertension affects a minority of treated hypertensive patients, yet the resulting target organ damage causes disproportionate morbidity and increased risk of cardiovascular events. The clinical features and efforts to adjust drug treatment in a resistant hypertensive patient are described. As demonstrated, serial hemodynamic measurements using thoracic bioimpedance may provide a rationale for selection of effective combination antihypertensive therapy. (c)2000 by CHF, Inc.

Posttransplantation hypertension related to calcineurin inhibitors.

Calcineurin inhibitors are a mainstay of transplant immunosuppression and commonly induce hypertension. They are highly lipid soluble and penetrate vascular smooth muscle cell membranes readily. Changes in vascular tone are universally observed during administration of these agents, particularly within the kidney, leading to diminished glomerular filtration and enhanced sodium retention. Disturbances of endothelial function are prevalent in many tissues, including stimulation of endothelin and impaired nitric oxide synthesis. Multiple additional pathways produce increased vasoconstriction, leading to an increase in arterial pressure. Clinical manifestations include disturbances in circadian blood pressure patterns, left ventricular hypertrophy, and acceleration of atherosclerotic and renal injury. Rapid increases in pressure occasionally produce accelerated hypertension and microangiopathic tissue damage. Principles of therapy require recognition of hazards of changing arterial pressures during calcineurin use and preferential use of vasodilating drugs, particularly dihydropyridine calcium channel blocking agents. Attention must be paid to interactions between antihypertensive agents and calcineurin inhibitor blood levels.

Hypertension after liver transplantation.

Hypertension developing after liver transplantation is nearly universal and likely reflects several pathogenic mechanisms. Foremost among these are altered vascular reactivity and vasoconstriction related to CSA, and probably FK506, administration, impaired GFR and sodium excretion, and the effects of steroids. This disorder is of both theoretical and practical importance in understanding blood pressure regulation in humans. Most importantly, it poses a considerable long-term cardiovascular risk for the transplant recipient. Recognition of acquired hypertension and timely intervention are among the primary management challenges for the transplant clinician.

Computed tomography-derived intrarenal blood flow in renovascular and essential hypertension.

The effect of renal artery stenosis on intrarenal perfusion and volume in renovascular hypertensive patients is unclear. Alterations in these attributes may ultimately be involved in deterioration of renal function. We measured whole kidney, cortical, and medullary perfusion and volume with electron beam computed tomography (EBCT) in 33 hypertensive patients, with well-preserved renal function, scheduled for renal angiography. EBCT-derived whole kidney perfusion was lower in patients with atherosclerotic renal artery stenosis (RAS; N = 20) than in fibromuscular dysplasia (FMD; N = 10) or essential hypertension (N = 28; P < 0.05), as was cortical perfusion (2.44 +/- 0.16 vs. 3.26 +/- 0.17 and 3.07 +/- 0.09 ml/min/cc tissue, respectively, P < 0.005), but medullary perfusion was similar. Whole kidney, cortical, and medullary perfusion correlated inversely with degree of stenosis in FMD, but not in atherosclerotic RAS. Renal volumes were similar. These results demonstrate that, in contrast to patients with FMD, in patients with atherosclerotic RAS the decrease in cortical perfusion is not directly related to the degree of stenosis in the main renal artery. Factors other than the stenosis itself may play a role in the pathophysiology of atherosclerotic RAS and associated renal failure.

Urinary endothelin and renal vasoconstriction with cyclosporine or FK506 after liver transplantation.

Transplant immunosuppression using either cyclosporine (CsA) or FK506 leads to renal vasoconstriction. To examine the role of endothelin (ET) in this process, we measured plasma and urinary ET before and at intervals for two years after liver transplantation. Urinary prostacyclin (as 6-keto-PG-F1 alpha), thromboxane, glomerular filtration rate and renal plasma flow were also measured. Forty-four patients were treated with CsA-based regimens and 31 patients with FK506-based regimens. Prednisone doses after one year were lower with FK506 (5.5 +/- 0.5 vs. 10.5 +/- 0.5 mg/day) by study design. Circulating plasma ET remained above normal, but not different from pre-transplant levels. Urinary ET was elevated before transplant (24.6 +/- 3.4 ng/day vs. normal 16 +/- 1.5 ng/day, P < 0.05) and rose further after transplantation (48.5 +/- 13 ng/day, P < 0.05), remaining elevated for two years. 6-keto-PG-F1 alpha fell from 2567 +/- 338 ng/day to subnormal levels and remained suppressed (1158 +/- 128 ng/day, P < 0.01). Over the same period GFR fell (84 +/- 3 ml/min to 60 +/- 3 ml/min, P < 0.01) and renal vascular resistance index rose (11,119 +/- 561 to 23,279 +/- 1692 d.s.cm-5.m-2, P < 0.01). Similar changes were observed both with CsA and FK506-based immunosuppression. No changes in ET were attributable to dihydropyridine calcium channel blockers. These results demonstrate that urinary ET changes independently from plasma ET after transplantation. Elevated ET and suppression of endothelium-derived prostacyclin persist with intense renal vasoconstriction for at least two years after transplant.