Clinically stable human renal allografts contain histological and RNA-based findings that correlate with deteriorating graft function.

BACKGROUND: Chronic rejection (CR) remains idiopathic, difficult to prospectively identify, and once detected, unresponsive to increased immunosuppression. We hypothesized that clinically stable human renal allografts have ongoing evidence of injury and immune activity, and that this correlates with the worsening of allograft function characteristic of CR. METHODS: The allografts of 40 stable renal allograft recipients were biopsied 2-3 years after transplantation. Biopsies were processed for histology and RNA extraction. RNA was evaluated by semi-quantitative RT-polymerase chain reaction for CD3y mRNA (a marker of T cell receptor turnover), and mRNA from cytokine genes previously shown to be transcribed during acute rejection: tumor necrosis factor-alpha, interferon-gamma, interleukin- (IL) 1beta, IL-2, IL-4, IL-6, and IL-8. Clinical parameters including urine protein and glomerular filtration rate were measured the day of biopsy. Findings were then compared with clinical outcome to establish associations between subclinical inflammation and graft dysfunction. Allograft function was measured again 2 years after biopsy and correlated with findings at the time of biopsy. RESULTS: Cytokine transcripts and histological evidence of injury were detected in more than two-thirds of stable grafts. The degree of the lymphocytic infiltrate correlated with the degree of proteinuria (P=0.034) and histological fibrosis (P=0.005). Similarly, the degree of intragraft CD3y transcription correlated with increasing proteinuria (P=0.043). IL-6 and IL-8 transcripts were also correlated with evidence of graft injury. After 2 years, those biopsies originally found to have evidence of fibrosis, tubular atrophy, or CD3gamma transcription had worsening graft function as determined by creatinine and glomerular filtration rate. CONCLUSIONS: These data demonstrate that significant injury and immune activity can be detected in patients who are stable on clinical grounds. Undetected subclinical graft injury may be a cause of chronic allograft rejection.

Maturation of pulmonary input impedance spectrum in infants and children with ventricular septal defect.

To determine whether pulmonary vascular disease can be detected in infants with ventricular septal defect (VSD) by the presence of an increase in the frequency of the impedance modulus minimum of the pulmonary input impedance spectrum, as has been implied for older children, spectra of 25 infants (2 years or younger) (group 1) were compared with spectra of 20 children (ages 2 to 7 years) (group 2). Groups were subdivided according to mean pulmonary artery (PA) pressure: those with moderate pressure levels (35 mm Hg or less, groups 1A and 2A) and those with high pressure levels (at least 40 mm Hg, groups 1B and 2B). Pulmonary vascular resistance, characteristic impedance and frequency of the modulus minimum were significantly lower in group 2A than in group 1A. The decrease in pulmonary vascular resistance and characteristic impedance with increasing age was consistent with body surface area increases; however, the shift in frequency of the modulus minimum could be more easily related to a decrease in the pulse wave velocity than to a shift in the primary reflection site. Pulmonary vascular resistance, characteristic impedance and the frequency of the first modulus minimum were comparable in groups 1B and 2B; however, none of the patients in group 1B had evidence of pulmonary damage, whereas 3 of 4 group 2B patients had microscopically apparent pulmonary vascular disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Infant pulmonary vascular model based on the pulmonary input impedance spectrum.

A mathematical model of the infant pulmonary vascular system was developed by altering an adult model to fit the hemodynamic properties of an infant pulmonary vascular bed. The model was designed for infants between the ages of 1 and 2 years with both normal and high mean pulmonary artery pressures (PAPs). The resulting infant model was evaluated on the basis of the computed parameters of cumulative length, volume and resistance of the pulmonary vascular bed, as well as on the basis of comparisons of the model spectra with actual computed spectra for ventricular septal defect patients who were of comparable age, had comparable mean PAPs and were not diagnosed as having pulmonary vascular disease. It was observed that the first minimum and first maximum in the modulus of the input impedance spectrum of the infant model for both normal and high mean PAPs occurred at a higher frequency than in the adult model. These observations led to the conclusion that there is a natural, age-related shift in the input impedance spectrum of infants which is not necessarily indicative of pulmonary impairment.