Simultaneous liver-kidney transplantation: a survey of US transplant centers.

Consensus recommendations have been published to help better define those patients who would benefit from simultaneous liver-kidney transplantation (SLK). We conducted a survey of transplant centers that perform SLK (n = 88, 65% response rate) to determine practice patterns in the United States. The majority of centers (73%) stated that they use dialysis duration whereas only 30% of centers use acute kidney injury duration as a criterion for determining need for SLK. Dialysis duration >4 weeks was used by 32% of centers, >6 weeks by 37% and >8 weeks by 32% of centers. Glomerular filtration rate (GFR) was estimated using the modified diet in renal disease (MDRD)-4 equation in roughly half of centers whereas the MDRD-6 equation was used by only 6%. In patients with chronic kidney disease, GFR < 40 mL/min was used by 24% of centers as a criterion for SLK transplants instead of the recommended threshold of < 30 mL/min. Regional differences in practices were also observed. This survey demonstrates significant variation in the criteria used for SLK among transplant centers, with few centers following the current published recommendations, and emphasizes the need for evidence-based guidelines and uniformity in studying renal dysfunction in liver transplant candidates.

Simultaneous liver-kidney transplantation summit: current state and future directions.

Although previous consensus recommendations have helped define patients who would benefit from simultaneous liver-kidney transplantation (SLK), there is a current need to reassess published guidelines for SLK because of continuing increase in proportion of liver transplant candidates with renal dysfunction and ongoing donor organ shortage. The purpose of this consensus meeting was to critically evaluate published and registry data regarding patient and renal outcomes following liver transplantation alone or SLK in liver transplant recipients with renal dysfunction. Modifications to the current guidelines for SLK and a research agenda were proposed.

Risk factors for late-onset cytomegalovirus disease in donor seropositive/recipient seronegative kidney transplant recipients who receive antiviral prophylaxis.

BACKGROUND: Cytomegalovirus (CMV) disease occurs frequently after cessation of antiviral prophylaxis in CMV-seronegative kidney transplant recipients from seropositive donors (D+R-), and the risk factors are incompletely defined. METHOD: We retrospectively assessed the incidence, clinical features, and risk factors for CMV disease in a cohort of D+R- kidney transplant recipients who received antiviral prophylaxis at a single US transplant center using descriptive statistics and Cox proportional hazards models. RESULTS: CMV disease developed in 29 of 113 (26%) D+R- patients at a median of 185 days (interquartile range 116-231 days) post transplant, including CMV syndrome (66%) and tissue invasive disease (34%). The incidence of CMV disease was higher in patients who underwent re-transplantation (57% vs. 24%) and this factor was independently associated with a higher risk of CMV disease in multivariable analysis (hazard ratio, 4.02; 95% confidence interval, 1.3-13; P = 0.016). Other demographic and transplant variables were not independently associated with a risk of late-onset CMV disease. CONCLUSIONS: Despite a comprehensive analysis of patient and transplant variables, only re-transplantation was identified as a risk factor for CMV disease in D+R- kidney transplant recipients who received antiviral prophylaxis, but had limited clinical predictive value. The development of novel laboratory markers to identify patients at greatest risk for CMV disease should be a priority for future studies.

Proceedings of Consensus Conference on Simultaneous Liver Kidney Transplantation (SLK).

A consensus conference sponsored by the American Society of Transplant Surgeons (ASTS), American Society of Transplantation (AST), United Network for Organ Sharing (UNOS) and American Society of Nephrology (ASN) convened to examine simultaneous liver-kidney transplantation (SLK). Directors from the 25 largest liver transplant programs along with speakers with recognized expertise attended. The purposes of this conference were to propose indications for SLK, to establish a prospective data registry and, most importantly, to recommend standard listing criteria for these patients. Scientific registry of transplant recipients data, and single center data regarding chronic kidney disease (CKD) and acute kidney injury (AKI) in conjunction with liver failure as a basis for SLK was presented and discussed. The consensus was that Regional Review Boards (RRB) should determine listing for SLK, as with other MELD exceptions, with automatic approval for: (i) End-stage renal disease with cirrhosis and symptomatic portal hypertension or hepatic vein wedge pressure gradient >/= 10 mm Hg (ii) Liver failure and CKD with GFR /= 2.0 mg/dL and dialysis >/= 8 weeks (iv) Liver failure and CKD and biopsy demonstrating > 30% glomerulosclerosis or 30% fibrosis. The RRB would evaluate all other requests to determine appropriateness.

Adolescent Transition to Adult Care in Solid Organ Transplantation: a consensus conference report.

Transition of care from pediatric to adult-oriented health care providers is difficult for children with special health care needs. Children who have received solid organ transplants and their providers experience the same difficulties and frustrations as children with other major illnesses. A consensus conference was organized by several transplant organizations to identify major issues in this area and recommend possible approaches to easing the process of transition for solid organ transplant recipients. This report summarizes the discussions and recommendations.

Effect of solidification rate on microstructure evolution in dual phase microalloyed steel.

In steels the dependence of ambient temperature microstructure and mechanical properties on solidification rate is not well reported. In this work we investigate the microstructure and hardness evolution for a low C low Mn NbTi-microalloyed steel solidified in the cooling rate range of 1-50 Cs-1. The maximum strength was obtained at the intermediate solidification rate of 30 Cs-1. This result has been correlated to the microstructure variation with solidification rate.

Mitoxantrone and cytosine arabinoside as treatment for acute myelogenous leukemia (AML) at first recurrence.

A total of 107 patients with newly diagnosed acute myeloblastic leukemia (AML) were referred to the ICRF Department of Medical Oncology at St Bartholomew's Hospital between August 1986 and July 1989. Of those referred, 92 (87%) were treated with remission induction chemotherapy comprising: Adriamycin, cytosine arabinoside (ara-C) and 6-thioguanine if aged < 60 years (57 patients) or mitoxantrone (MTN) and ara-C if aged > 60 years (35 patients). Of those treated, 54 (58%) entered complete remission (CR). Recurrent AML developed in 38 out of these 54 patients (70%) of whom 25 aged 19-73 years (median 50 years) subsequently received MTN and ara-C as reinduction therapy. The 19 younger patients (under 60 years old) received MTN at 12 mg/m2, intravenously, daily for 5 days and ara-C at 100 mg/m2, intravenously, twice daily for 7 days. The six older patients received the same ara-C schedule but the dose of MTN was reduced to 10 mg/m2 for 5 days. Second CR was achieved in 16 out of 25 patients (64%) [12/19 (63%) and 4/6 (67%) for patients aged under or over 60 years, respectively]. Eight of the patients in whom second CR was achieved were aged under 50 years and were thus eligible for additional consolidation comprising myeloablative therapy with autologous bone marrow transplantation (ABMT). Four patients actually received the latter treatment: two remain in second CR at 21 and 46 months. Three of the remaining eight patients aged > 50 years in whom second CR was achieved remain in second CR 8 to 43 months later. Censored for myeloablative therapy + ABMT, the overall median duration of second CR was 5 months. Although remissions tended to be short, in younger patients the possibility of proceeding to myeloablative therapy with autologous bone marrow support makes the regimen worthwhile and, even in older patients, it was sometimes possible to achieve prolonged second remissions.

Diagnosing pneumonia by physical examination: relevant or relic?

BACKGROUND: The reliability of chest physical examination and the degree of agreement among examiners in diagnosing pneumonia based on these findings are largely unknown. OBJECTIVES: To determine the accuracy of various physical examination maneuvers in diagnosing pneumonia and to compare the interobserver reliability of the maneuvers among 3 examiners. METHODS: Fifty-two male patients presenting to the emergency department of a university-affiliated Veterans Affairs medical center with symptoms of lower respiratory tract infection (cough and change in sputum) were prospectively examined. A comprehensive lung physical examination was performed sequentially by 3 physicians who were blind to clinical history, laboratory findings, and x-ray results. Examination findings by lung site and whether the examiner diagnosed pneumonia were recorded on a standard form. Chest x-ray films were read by a radiologist. RESULTS: Twenty-four patients had pneumonia confirmed by chest x-ray films. Twenty-eight patients did not have pneumonia. Abnormal lung sounds were common in both groups; the most frequently detected were rales in the upright seated position and bronchial breath sounds. Relatively high agreement among examiners (kappa approximately 0.5) occurred for rales in the lateral decubitus position and for wheezes. The 3 examiners' clinical diagnosis of pneumonia had a sensitivity of 47% to 69% and specificity of 58% to 75%. CONCLUSIONS: The degree of interobserver agreement was highly variable for different physical examination findings. The most valuable examination maneuvers in detecting pneumonia were unilateral rales and rales in the lateral decubitus position. The traditional chest physical examination is not sufficiently accurate on its own to confirm or exclude the diagnosis of pneumonia.

Liver enzymes and clustering cardiometabolic risk factors in European adolescents: the HELENA study.

OBJECTIVES: This study aimed to explore the associations of liver biomarkers with cardiometabolic risk factors and their clustering, and to provide reference values (percentiles) and cut-off points for liver biomarkers associated with high cardiometabolic risk in European adolescents. METHODS: Alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), aspartate aminotransferase to ALT ratio (AST/ALT), waist circumference, blood pressure, triglycerides, high-density lipoprotein cholesterol and insulin were measured in 1084 adolescents. We computed a continuous cardiometabolic risk score and defined the high cardiometabolic risk. RESULTS: Higher ALT and GGT and lower AST/ALT were associated with adiposity and with the number of adverse cardiometabolic risk factors (Ps < 0.05). Higher GGT and lower AST/ALT were associated with higher cardiometabolic risk score (Ps < 0.001) in males and females, and ALT only in males (Ps < 0.001). Gender- and age-specific percentiles for liver biomarkers were provided. Receiver operating characteristic analyses showed a significant discriminatory accuracy of AST/ALT in identifying the low/high cardiometabolic risk (Ps < 0.01) and thresholds were provided. CONCLUSIONS: Higher GGT and lower AST/ALT are associated with higher cardiometabolic risk factors and their clustering in male and female European adolescents, whereas the associations of ALT were gender dependent. Our results suggest the usefulness of AST/ALT as a screening test in the assessment of adolescents with high cardiometabolic risk and provide gender- and age-specific thresholds that might be of clinical interest.

The neuroendocrine effects of interleukin-2 treatment.

Observations of neuropsychiatric changes in patients receiving interleukin-2 (IL-2) led us to examine the effects of IL-2 administration on the stress-related hormones, beta-endorphin, ACTH, cortisol, and CRH. We evaluated 30 cancer patients who received immunotherapy with IL-2 or IL-2 plus lymphokine-activated killer (LAK) cells. Blood samples were taken immediately before and 4 and 8 h after infusion of IL-2 or IL-2 plus LAK cells. IL-2 stimulated increased hormone levels 4 h after infusion compared with those before therapy and with basal levels in normal volunteers at the following magnitudes: beta-endorphin, 10-fold; ACTH, 20-fold; and cortisol, 2-fold. The effect of IL-2 was not altered in patients also receiving LAK cells. An effect of treatment course was noted, with higher stimulated values seen 4 h after IL-2 in the second treatment course compared with those after the first course [change (delta) in beta-endorphin, 101 vs. 11 fmol/mL; delta ACTH, 138 vs. 8 pmol/L; delta cortisol, 414 vs. 218 nmol/L]. We conclude that IL-2 treatment induces the release of neuroendocrine hormones and that a significant increase in hormonal stimulation occurs upon reexposure to IL-2.

Hyperreninemic hypoaldosteronism in the critically ill: a new entity.

To define the changes in adrenal gland function during critical illness, we evaluated 28 severely ill patients with persistent hypotension who were hospitalized in a medical intensive care unit. The patients had increased plasma cortisol (mean +/- SE, 40.1 +/- 10.1 micrograms/dl). PRA was increased in all subjects (21.6 +/- 7.2 ng/ml.h); however, the plasma aldosterone concentration was inappropriately low in 18 of the subjects, with values ranging from 1-9 ng/dl, despite normal serum potassium concentrations (4.3 +/- 0.1 meq/liter) and increased concentrations of the aldosterone percursor, 18-hydroxycorticosterone. These 18 patients had hypotension associated with major infections and a high mortality rate (78%). Infusions of ACTH or angiotensin II were associated with a normal aldosterone response in only 2 of the 14 patients tested, also suggesting that the defect was probably at the level of the zone glomerulosa cell. Although infection was a common underlying illness, no other factors, such as dopamine administration, decreased angiotensin-converting enzyme activity, or increased aldosterone clearance, could be implicated as the cause of the phenomena. Thus, selective hypoaldosteronism in the presence of high renin levels exists in a substantial percentage of hypotensive critically ill patients.

Salivary cortisol: a practical method for evaluation of adrenal function.

Salivary cortisol represents a simple, noninvasive, stress-free measure that can greatly facilitate the longitudinal study of hypothalamic-pituitary-adrenal axis activity in patients with psychiatric disorders. By means of a slight modification of a commercially available radioimmunoassay kit, we studied the stability of salivary cortisol under different conditions, as well as the relationship between plasma and salivary cortisol under basal circadian conditions and following stimulation (CRH) and suppression (dexamethasone). We observed that salivary cortisol was quite stable at room temperature without centrifugation and that salivary and plasma cortisol values were highly correlated. Additionally, we observed a close correspondence in circadian and ultradian fluctuations in salivary and plasma cortisol. The salivary cortisol response to ovine and human CRH was similar to that observed with plasma cortisol, but was greater in magnitude. Finally, employing a plasma criterion as the standard, salivary measures identified 48% of the nonsuppressed Dexamethasone Suppression Tests (DSTs) and 97% of the suppressed DSTs.

Elevated basal and thapsigargin-stimulated intracellular calcium of platelets and lymphocytes from bipolar affective disorder patients measured by a fluorometric microassay.

BACKGROUND: A number of investigators have reported finding elevated basal and stimulated intracellular calcium levels in the platelets or lymphocytes of bipolar disorder patients. METHODS: Intracellular calcium was measured by a micro fura-2 fluorometric method in the platelets and lymphocytes of 30 affective disorder patients and 14 control subjects. RESULTS: We observed significantly elevated basal calcium concentrations in bipolar patient platelets and lymphocytes compared to control subjects. Bipolar patient platelet calcium responses to thrombin, serotonin, and thapsigargin were also significantly greater than control subjects. The peak calcium levels of lymphocytes of bipolar patients were greater than control subjects only when stimulated by thapsigargin. There were significant differences between bipolar and unipolar patients in basal and thapsigargin-stimulated calcium measures but not between bipolar I and bipolar II patients. Unmedicated versus medicated calcium measures were not significantly different. We also found little correlation between calcium measures and the severity of mood rating. CONCLUSIONS: Using this method, we were able to confirm and extend the work of others, indicating altered intracellular calcium homeostasis in the blood cells of bipolar disorder patients. In addition, our data suggest that storage operated calcium channels may be the source of the elevated intracellular calcium in platelets and lymphocytes of bipolar patients.

The TRH stimulation test in Alzheimer's disease and major depression: relationship to clinical and CSF measures.

A blunted thyroid-stimulating hormone (TSH) response to exogenous thyrotropin-releasing hormone (TRH) has been reported to occur consistently in patients with major depression and less consistently in patients with Alzheimer's disease (AD). In this study we compared the TSH response to TRH in a large group (n = 40) of AD patients, elderly patients with major depression (n = 17), and age-matched controls (n = 14) to further characterize how it may relate to clinical variables, baseline thyroid function tests, and cerebrospinal fluid measures. Comparisons of TRH stimulation test response across all three groups revealed that patients with major depression had lower stimulated TSH levels (delta maxTSH) (p less than 0.02) and higher (though still within normal limits) mean thyroxine (T4) levels (p less than 0.05) than the AD patients or controls. AD patients with a blunted TSH response had a significantly higher mean free T4 (FT4) level (p less than 0.03) and tended to be more severely demented (p less than 0.01) than those with a nonblunted response.

CSF monoamine metabolites and somatostatin in Alzheimer's disease and major depression.

Decreased cerebrospinal fluid (CSF), somatostatinlike immunoreactivity (SLI) and alterations in the CSF monamine metabolites 3-methoxy-4-hydroxyphenylethylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) have been reported in patients with probable Alzheimer's disease (AD) and in patients with major depression. In this study, we found CSF SLI to be significantly lower in a large group of AD patients (n = 60) and in a group of age-matched patients with major depression (n = 18) as compared with normal controls (n = 12). Mean CSF, MHPG, 5-HIAA, and HVA levels were not significantly different among diagnostic groups. Within a group of "depressed" AD patients, CSF levels of 5-HIAA showed a significant positive correlation (p = 0.03) with CSF SLI; a similar relationship was found within the group of patients with major depression. Further exploration of the relationship between the somatostatin and serotonin systems may provide clues as to how neuropeptides interact with monoamine neurotransmitters and what role they have in depression.

CSF somatostatin in obsessive-compulsive disorder.

OBJECTIVE: Because the central administration of somatostatin to experimental animals produces behaviors with some similarities to the compulsions of patients with obsessive-compulsive disorder and because serotonin reuptake inhibitors have been reported to reduce brain content of somatostatin, the authors examined central somatostatin activity in patients with obsessive-compulsive disorder. METHOD: CSF for measurement of somatostatin was obtained from 15 drug-free outpatients with obsessive-compulsive disorder and 27 normal volunteers. RESULTS: The mean CSF somatostatin level was significantly higher in the patients with obsessive-compulsive disorder than in the normal subjects. CONCLUSIONS: Although the functional significance of this finding is unknown, these data are consistent with a role for somatostatin in the clinical symptomatology of obsessive-compulsive disorder and its response to neuropharmacological agents. The high levels of CSF somatostatin reported here in a patient subgroup whose predominant symptoms consisted of overly focused, perseverative thought processes are in contrast to the consistently low levels of CSF somatostatin seen in patients with a spectrum of disorders characterized by substantial cognitive deficits.

Nimodipine increases CSF somatostatin in affectively ill patients.

Preliminary evidence suggests that nimodipine, an L-type calcium channel blocker, is effective in treating some patients with rapidly cycling affective disorders and some phases of Alzheimer's disease, i.e., two syndromes associated with transient or permanent reductions in cerebrospinal fluid (CSF) somatostatin, respectively. CSF somatostatin (SRIF) was measured in 14 affectively ill patients while they were medication-free and during chronic nimodipine treatment. CSF somatostatin significantly increased in patients during active nimodipine treatment compared with ones in the medication-free state. The current findings raise the possibility that nimodipine-induced increases in CSF somatostatin could potentially contribute to its spectrum of efficacy on neuropsychiatric disorders associated with cognitive or affective impairment. Further clinical and preclinical studies are indicated to elucidate the potential mechanisms involved in the elevation of CSF SRIF, whether it is reflected in regional changes in brain, and its possible relevance to nimodipine's clinical actions.

Enzyme potentiated radioimmunoassay (EPRIA): a sensitive third-generation test for the detection of hepatitis B surface antigen.

A sensitive, specific immunoassay for detection of hepatitis B surface antigen (HBsAg) is described. The assay combined enzyme-linked immunosorbent assay and solid-phase radioimmunoassay and is termed enzyme potentiated radioimmunoassay (EPRIA). HBsAg was quantitated by enzymatic conversion of L[14C]glutamic acid to 14CO2 and gamma-aminobutyric acid by glutamate decarboxylase (GDC) conjugated wih goat anti-HGs IgG. Conjugation of IgG and GDC was by a thiol-disulfide bond exchange reaction after reacting N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP) with each reagent. A positive/negative ratio of 2.2 was established as significant by examination of 40 normal sera negative for HBsAg. This value was the mean cpm plus 3 standard deviations. By an identical statistical analysis of sensitivity, EPRIA was found to be approximately 100-fold more sensitive than Ausria II (Abbott Laboratories, North Chicago, IL).

Bone pain that responds to calcium channel blockers. A retrospective and prospective study of transplant recipients.

A severe episodic bone pain syndrome of unknown cause was first described in renal transplant recipients in France and associated with the use of cyclosporine. We have retrospectively and prospectively evaluated this pain syndrome in our transplant patients. This pain is bilateral, of acute onset and episodic, primarily involving the knees and/or ankles. It usually occurs at night or with recumbency, and is often relieved with elevation or walking. Physical examination of the affected areas is unrevealing. Kidney, liver, pancreas, heart, lung and combined organ transplant recipients on cyclosporine were available from the University of Washington Transplant Services and were retrospectively evaluated by chart review (n = 351) or prospective clinical evaluation (n = 38) for evidence of this clinical syndrome. In the retrospective chart review, 19.1% of patients had episodes of bone pain. The highest prevalence occurred in renal transplant recipients (27.7%). The bone pain syndrome was documented in the charts of 14 patients who subsequently developed significant osteonecrosis. Prospectively, 21 of 22 patients with the bone pain syndrome experienced complete relief of this pain upon treatment with calcium channel blockers (95.4% response rate). The pathophysiology of this bone pain syndrome is unknown, although its response to the vasodilatory effects of calcium channel blockers suggests a vascular etiology.

Successful treatment of severe hepatitis C-associated pulmonary vasculitis in a liver transplant recipient.

BACKGROUND: We report the clinical course of a patient who developed fever, hypoxia, and bilateral pulmonary infiltrates two and a half years after orthotopic liver transplantation (OLT) for cirrhosis due to hepatitis C. The patient had a history of hepatitis C-associated vasculitis manifested by purpuric skin rashes, renal abnormalities, and elevated cryoglobulins, and was receiving interferon-alpha at the time of presentation. RESULTS: The results of bronchoscopy with bronchoalveolar lavage were unrevealing, and open lung biopsy revealed active small vessel vasculitis. The patient responded dramatically to plasmapheresis and the addition of high-dose corticosteroids with resolution of hypoxia, pulmonary infiltrates, and glomerulonephritis. This is, to our knowledge, the first report of the successful treatment of hepatitis C-associated pulmonary vasculitis after OLT. CONCLUSIONS: We conclude that hepatitis C-associated pulmonary vasculitis should be included in the differential diagnosis of a patient presenting with fever, hypoxia, and pulmonary infiltrates after OLT for hepatitis C. Treatment with plasmapheresis and high-dose corticosteroids may be effective in patients with this disorder.