Urinary biomarkers of early renal injury in antiretroviral-naïve HIV-positive persons in Shanghai, China: comparison with the general population.

OBJECTIVES: People living with HIV (PLWH) have a high risk of kidney injury. Measurement of serum creatinine, along with proteinuria, is not sensitive to detect early kidney injury. Here, we investigated novel urinary biomarkers of early renal injury in PLWH. METHODS: We performed a cross-sectional study of 166 antiretroviral-naïve PLWH and 99 HIV-negative persons who all had an estimated glomerular filtration rate > 90 mL/min/1.73 m2 . We compared the levels of seven urinary biomarkers between the two groups using the propensity score matching (PSM) approach and explored the risk factors associated with elevated urinary biomarkers in PLWH. RESULTS: Eighty-three pairs were successfully matched based on PSM. Compared with the HIV-negative group, the HIV-positive group had higher ratios of N-acetyl-ß-D-glucosaminidase (NAG) to urine creatinine (UCr), alpha1-microglobulin (α1-M) to UCr, kidney injury marker-1 (KIM-1) to UCr, neutrophil gelatinase-associated lipocalin to UCr, and epidermal growth factor to UCr, whereas the Tamm-Horsfall protein to UCr ratio and the abnormal albumin to UCr ratio were not significantly different. Positive correlations were observed between HIV RNA level and NAG: UCr (rs  = 0.32; P < 0.001) and α1-M:UCr (rs  = 0.24; P = 0.002) ratios, and negative correlations were observed between CD4 cell count and NAG:UCr (rs  = -0.34; P < 0.001), KIM-1:UCr (rs  = -0.16; P = 0.042) and α1-M:UCr (rs  = -0.36; P < 0.001) ratios. In multivariate linear regression analyses, older age, lower total cholesterol and higher HIV RNA were independently associated with higher NAG:UCr; older age, lower total cholesterol and lower CD4 cell count were independently associated with higher α1-M:UCr. CONCLUSIONS: In comparioson with HIV-negative participants, PLWH were more likely to have tubular injury. Early antiretroviral treatment might mitigate the development of kidney injury.

Correlates of brain edema in uncontrolled IDDM.

Blood glucose, plasma sodium, bicarbonate (HCO3-), vasopressin, and hematocrit were monitored before and during treatment in patients with uncontrolled insulin-dependent diabetes mellitus (IDDM). These parameters were correlated with simultaneous serial cranial computed tomography readings of brain edema. Six of seven patients had positive computed tomography readings for brain edema on admission. Initial brain edema correlated directly with blood glucose (r = 0.79, P = 0.033) and inversely with HCO3- (r = -0.76, P = 0.047). At 6 h, brain edema still correlated with acidosis (HCO3-; r = -0.79, P = 0.033) but no longer with blood glucose. At that time, however, brain edema correlated with the rate of change in blood glucose (r = 0.915, P = 0.005). Results of interactive stepwise regression analysis suggest that the change in the calculated effective plasma osmolality plays a predominant role in the progression of brain edema during therapy (r = 0.995, P less than 0.001). Thus, although hyperglycemia and acidosis probably predispose to diabetic brain edema, osmotic factors may be major predictors of its evolution. No relationships were detected between brain edema and initiation of insulin therapy, plasma vasopressin, or changes in hematocrit. The factors responsible for initial brain edema and its progression, statistically identified in this study, require reassessment of common theories that attribute brain edema exclusively to therapy.

Low-dose daily subcutaneous interleukin-2 in combination with highly active antiretroviral therapy in HIV+ patients: a randomized controlled trial.

PURPOSE: Previous studies with intermittent interleukin-2 (IL-2) therapy using intermediate and high levels of IL-2 have demonstrated significant increases in the CD4 + T cell count in HIV-infected patients. Intermittent regimens are amenable to outpatient use, but severe adverse events are frequently experienced with intermediate- and high-dose levels of IL-2. Therefore in this study, the effect of daily, subcutaneous low-dose IL-2 therapy on safety and immunological endpoints was investigated to determine whether immunological benefit could be achieved without toxicity in HIV-infected patients also receiving highly active antiretroviral therapy (HAART). METHOD: A total of 115 patients were enrolled in the trial. Fifty-six asymptomatic HIV-infected patients who had CD4 + T cell counts less than 300 cells/microL at screening and a stable HIV viral load received low-dose IL-2 (1.2 million IU [MIU]/m 2 beginning dose) once daily in conjunction with HAART (IL-2 group). Fifty-nine patients received HAART alone (control group). RESULTS: A dramatic effect of IL-2 on the natural killer (NK) cell population was observed with mean increases of 156 cells/microL in the IL-2 group compared to 19.93 cells/microL in the control group (p <.001). Additionally, IL-2-treated patients experienced a statistically significant increase in the mean percentage of CD4 + T cells (3.52% increase) when compared to control patients (1.33% increase) (p <.001). The expanded CD4 + T cell population was primarily of the naive phenotype, with mean increases of 4.53% for the IL-2 group and 0.31% for the control group (p <.001 for between-group difference). In addition, a higher proportion of IL-2-treated patients (67%) compared to control patients (33%) achieved increases of greater than 50% in the CD4+ T cell count (p =.08). Adverse events of grade 3 or grade 4 toxicity were infrequent in the current study and were substantially lower by comparison to those in studies of intermittent dose IL-2 therapy. Also, negligible changes in the HIV viral load from baseline to final measurement were observed in both groups. A trend toward a reduced number of modifications of antiretroviral therapy was apparent in the IL-2 group when compared to control patients. CONCLUSION: Daily, low-dose subcutaneous IL-2 therapy in conjunction with HAART is safe and well tolerated and is effective in expanding lymphocyte cell types including NK cells and naive T cells in individuals who have <300 CD4+ T cells.

Cranial CT in children and adolescents with diabetic ketoacidosis.

To determine the effects of diabetic ketoacidosis on the brain, we studied nine consecutive patients between the ages of 6 and 17 years by performing cranial CT on three occasions: on admission, before treatment; 6-8 hr after beginning treatment; and 7 days after admission. Both the pretreatment scans and those at 6-8 hr showed significantly reduced size of the lateral and third ventricles in comparison with the 7-day scans. A comparison of the pretreatment scans with those done at 6-8 hr showed no statistically significant differences. We conclude that the cerebral swelling of diabetic ketoacidosis is usually present before treatment.

Poisoning.

Knowledge of the toxicologic nature of ingested substances provides a proper framework for general and specific therapies best suited to meet the needs of the patient. Monitoring and direct observation provided in the PICU can aid proper therapy for many intoxicants. Good supportive care coupled with specific pharmacotherapy will provide the best chance for a successful outcome.

Epoetin alfa therapy for anaemia in HIV-infected patients: impact on quality of life.

To evaluate the effect of epoetin alfa on the quality of life (QOL) of HIV-infected patients in the community setting, 221 anaemic (haemoglobin < or = 11 g/dl) HIV-positive patients from community-based treatment centres and physicians' offices were treated with epoetin alfa (100-300 units/kg subcutaneously 3 times a week) in a 4-month, open-label, non-randomized, phase IV trial. Epoetin alfa therapy significantly (P<0.01) increased and maintained haemoglobin levels (mean increase=2.5 g/dl; n=207); the improvement in haemoglobin levels was independent of changes in CD4+ cell counts. Transfusion requirements were also significantly reduced from 20% to 5% of patients (P<0.01). Mean total QOL score measured by the Functional Assessment of HIV Infection (FAHI) scale and Physical Well-Being subscale score improved significantly (P<0.05). QOL improvements associated with increases in haemoglobin were independent of changes in CD4+ counts and baseline anaemia severity. Adverse events observed during epoetin alfa therapy were consistent with HIV disease and not likely due to the drug. Epoetin alfa therapy should be considered a treatment option for HIV-infected patients with mild-to-moderate anaemia.

Determination of rebreathing oxygen consumption and derivation of oxygen delivery in intubated mongrel dogs after phlebotomy and isoproterenol infusion.

This study attempted to determine the correlation between oxygen consumption (VO2), pulmonary-capillary blood flow (QEPC), and oxygen delivery (DO2) by rebreathing and invasive techniques obtained over a range of hemoglobin concentration and cardiac output. Twenty mongrel dogs were instrumented with central arterial and venous catheters to determine DO2 by thermodilution cardiac output and standard formulas. The animals were administered isoproterenol in doses that increased DO2 and subsequently were serially phlebotomized by 30%, 40%, and 50% to decrease DO2. All animals were studied using a rebreathing technique to determine noninvasively VO2, QEPC, and DO2. Sixteen dogs completed the experimental protocol. A correlation analysis was carried out for VO2, QEPC, and DO2 obtained by the rebreathing and invasive methods. Thermodilution cardiac output increased from 3.91 +/- 1.77 L/min at baseline to 8.19 +/- 2.50 L/min during isoproterenol infusion. Hemoglobin varied from 12.21 +/- 1.26 gm% at baseline to 5.21 +/- 1.36 g% at 50% phlebotomy. Over this range of conditions, significant correlations were obtained between rebreathing VO2 and invasive VO2 (r = 0.80, p < 0.0001), rebreathing QEPC and invasive QEPC (r = 0.79, p < 0.0001), and rebreathing DO2 and invasive DO2 (r = 0.82 p < 0.0001). These data demonstrate that the rebreathing technique can be used to monitor oxygen metabolism over wide ranges of DO2.

HIV-associated wasting in the HAART era: guidelines for assessment, diagnosis, and treatment.

Wasting (malnutrition) and lipodystrophy are the two major nutritional alterations in human immunodeficiency virus (HIV)-infected individuals. Both wasting and lipodystrophy may involve a decrease in body fat content, while wasting-but not lipodystrophy-also includes the loss of lean body mass. Lipodystrophy has made the identification of wasting increasingly more difficult. The diagnosis of wasting depends on a definition of the condition that takes into account sex and cultural differences, as well as measurements of body cell mass. Patient management involves a concurrent, comprehensive approach designed to restore lost body cell mass and weight. The authors make recommendations for defining, diagnosing, and treating HIV-associated wasting. Specific therapies include testosterone replacement, other anabolic steroids, and recombinant human growth hormone. Other adjunctive measures, such as progressive resistance exercise and cytokine modulation, may also be utilized. Expected outcomes from effective treatment include restored body cell mass, improvement in quality of life, and reduced rates of hospitalization. Future directions for research should address the need for optimal treatment strategies.

Extracorporeal whole body hyperthermia treatments for HIV infection and AIDS.

Whole body hyperthermia therapy (WBHT) is the elevation of the core body temperature to 42 degrees C. In vitro studies have confirmed that 42 degrees C is cytocidal for virally infected lymphocytes, and even more effective when heating is repeated 4 days later. The safety and efficacy of two successive sessions of WBHT (4 days apart) was evaluated in 30 patients with AIDS (not on protease inhibitors), randomized to: 1) untreated controls, 2) low temperature WBHT for 1 hour at 40 degrees C and repeated 96 hours later, and 3) high temperature WBHT for 1 hour at 42 degrees C and repeated 96 hours later. The sorbent suspension in the ThermoChem System (HemoCleanse, West Lafayette, IN) system automatically controlled blood phosphate, calcium, and other electrolyte concentrations during WBHT. In 1 year of follow-up after WBHT, there were positive effects of the therapy on frequency of AIDS defining events, Karnofsky score, and weight maintenance. However, effects on plasma HIV RNA and CD4 counts were transient. Two successive WBHT treatments were performed in four patients who were on protease inhibitor/triple drug therapy, but had suboptimal response. In follow-up for 6 months, plasma HIV RNA and CD4 improved after WBHT, and the patients remained clinically well. This WBHT may have specific advantages in patients with suboptimal response to protease inhibitor therapy.

HIV-associated wasting in the era of HAART: a practice-based approach to diagnosis and treatment.

Wasting remains an important, yet often overlooked, condition in HIV-infected patients receiving HAART. Successful office-based management depends on early diagnosis by bioelectric impedance analysis and on a multifaceted approach to treatment. Immediate goals include controlling viral load, correcting any immediate causes of wasting, and improving nutritional intake. Should wasting persist despite these measures, various therapies may be initiated. These include testosterone replacement therapy in hypogonadal patients, recombinant human growth hormone, anabolic steroids, progressive resistance exercise, and experimental therapies. Early treatment of HIV-associated wasting restores body cell mass, improves quality of life, and reduces the frequency of opportunistic infections and hospitalizations.

Esophageal-aortic erosion associated with double aortic arch and tracheomalacia. Experience with 2 infants.

Patients with double aortic arch may require lengthy intubation for ventilatory support. The need for endotracheal and nasogastric intubation may be prolonged in such patients because of associated tracheomalacia. Iatrogenic tracheal or esophageal erosion with subsequent aortic fistulization is an unusual but catastrophic complication that may result from such intubation. We report the cases of 2 infants with double aortic arch and tracheomalacia who developed iatrogenic esophageal-aortic erosion. This complication was successfully managed in 1 of the infants. We conclude from our experience that the important steps in preventing this complication include 1) expediting the exclusion of upper-airway compromise in intubated infants who have a presentation characteristic of bronchospastic airway disease (hyperinflation and hypercapnia) that seems unresponsive to usual therapeutic measures; and 2) expediting the diagnosis of vascular ring in order to minimize the duration of dual tracheal and esophageal intubation. Effective management of this problem, once established, requires primary closure of the esophageal perforation, removal of the nasogastric tube, interposition of thick viable tissue between the esophagus and the aorta, and decompressive gastrostomy and feeding jejunostomy. Concomitant aortopexy may be appropriate.

Partnerships in health care: creating a strong value chain.

The health care climate is one of stormy relations between various entities. Employers, managed care organizations, hospitals, and physicians battle over premiums, inpatient rates, fee schedules, and percent of premium dollars. Patients are angry at health plans over problems with access, choice, and quality of care. Employers dicker with managed care organizations over prices, benefits, and access. Hospitals struggle to maintain operations, as occupancy rates decline and the shift to ambulatory care continues. Physicians strive to assure their patients get quality care while they try to maintain stable incomes. Businesses, faced with similar challenges in the competitive marketplace, have formed partnerships for mutual benefit. Successful partnerships are based upon trust and the concept of "win-win." Communication, ongoing evaluation, long-term relations, and shared values are also essential. In Japan, the keiretsu contains the elements of a bonafide partnership. Examples in U.S. businesses abound. In health care, partnerships will improve quality and access. When health care purchasers and providers link together, these partnerships create a new value chain that has patients as the focal point.

Lumbar puncture in the presence of increased intracranial pressure: the real danger.

Examination of cerebrospinal fluid remains a mainstay of the diagnosis of many acute central nervous system illnesses, including meningitis, encephalitis, and polyneuropathies such as Guillain-Barré syndrome. Although generally considered innocuous, there may be considerable danger when lumbar puncture is performed in the presence of increased intracranial pressure, especially when a mass lesion is present. We review the literature surrounding the danger of lumbar puncture when intracranial pressure is increased and discuss our approach to the problem in lieu of the advent of computerized tomographic scanning.

Use of brainstem auditory evoked potentials in pediatric brain death.

Brainstem auditory evoked potentials (BAEPs) were examined prospectively in ten clinically brain-dead and 13 comatose nonbrain-dead children. All clinically brain-dead children failed to demonstrate brainstem impulse transmission, displaying no waves or only wave I. The comatose, nonbrain-dead children maintained evidence of brainstem electrical activity, manifested by at least two waveforms. This suggests that BAEPs are a useful noninvasive method of supporting the clinical diagnosis of brain death in children.

Shedding light on the use of heat to treat HIV infections.

Considering the lack of effectiveness of current therapies to treat HIV disease, the authors present observations that provide a strong cogent argument for critically designed and meticulously performed clinical trials employing whole body hyperthermia with or without other therapeutic modalities. Only as a result of such clinical trials will it be possible to fairly evaluate the role of hyperthermia as a potential therapy for treatment of chronic HIV infection.

Coronary vasoactivity of acetate in dog and guinea-pig.

This study compares the coronary vasoactivity of acetate in the blood-perfused heart of the open-chest dog and in the buffer-perfused guinea-pig heart. In the dog acetate is a weak but probably fully efficacious coronary agonist. Direct intracoronary infusions of isosmolar Na acetate caused dose-dependent coronary vasodilation and decreased transcoronary O2 extraction, resulting in an increase in cardiac O2 usage of up to 40%. Acetate raised coronary flow to at least 50% above control in 63 of 67 dogs but caused maximum coronary vasodilation (400% of control) in only 39 of the 67. The frequency distribution of the acetate EC-20 decreased monotonically from a mode at less than 1 mM over a range extending to greater than 6 mM, suggesting a single population of animals characterized by a rather wide range of sensitivity to acetate. Theophylline antagonized acetate vasodilation, in support of the idea that adenosine mediates the coronary effects of acetate. In the guinea-pig heart, acetate in concentrations up to 10 mM caused minimal increases in coronary flow that were completely accounted for by the small change in O2 usage that resulted from switching from glucose to acetate the main energy source. Acetate (10 mM) elicited a small release of adenosine and its degradation products.