Patterns of chronic injury in pediatric renal allografts.

BACKGROUND: In pediatric recipients, the pathophysiology of chronic renal allograft injury is poorly understood. METHODS: We studied the evolution and determinants of tubulointerstitial, vascular, and glomerular injury in 240 pediatric protocol renal allograft biopsies during the first 5 years posttransplant. RESULTS: Chronic tubulointerstitial injury (ci, ct) developed predominantly during the first 12 months posttransplant, whereas chronic vascular damage (cv, and arteriolar hyalinosis [ah]) and global glomerulosclerosis (gs) became increasingly prevalent at 25 to 36 months and beyond. Chronic interstitial lesions were associated with acute rejection and borderline histology (odds ratio [OR] 2.3, P<0.04), recipient body surface area less than 1.0 m2 (OR 3.6, P<0.05), and obesity (OR 2.0, P<0.03). Determinants of ct were acute rejection (OR 2.6, P=0.02) and acute tubular necrosis (OR 2.8, P<0.04). Vascular fibrous intimal thickening and ah were associated with donor hypertension (OR 3.6, P=0.001) and recipient body surface area less than 1.0 m (OR 2.6, P=0.02), respectively. The severity of ah correlated with the incidence of gs (r=0.32, P<0.0001), with 7.8% gs for ah0, 14.3% gs for ah1, 60.0% gs for ah2, and 95.5% gs for ah3 (median values). Antibody induction conferred protection from ci (OR 0.31, P=0.008), ct (OR 0.33, P=0.002), and ah (OR 0.12, P<0.001) progression. CONCLUSIONS: By 5 years posttransplant, pediatric renal allografts manifest a substantial burden of tubulointerstitial and microvascular injury. These lesions are associated with donor hypertension, acute inflammation, renal hypoperfusion, obesity, and calcineurin inhibitor toxicity. The pervasiveness and rapid progression of microvascular lesions at 25 to 36 months suggest that attempts at reducing calcineurin inhibitor exposure should be made before two years posttransplant.

Trials of new germ cell immunohistochemical stains in 93 extragonadal and metastatic germ cell tumors.

Organic cation transporter 3/4 (OCT3/4) is a transcription factor of embryonic stem cells; c-kit (CD117) is a tyrosine kinase receptor implicated in seminoma carcinogenesis. Their reactivity is well characterized in testicular, but not extragonadal and metastatic, germ cell tumors. A total of 93 germ cell tumors (41 seminoma, 22 embryonal carcinoma, 18 teratoma, and 12 yolk sac tumor) were obtained from the central nervous system (30), mediastinum (23), retroperitoneum/abdomen (31), and other locations (9). Immunohistochemical staining for c-kit, placental-like alkaline phosphatase (PLAP), OCT3/4, and new markers D2-40 and AP-2gamma was performed on seminomas; CD30 and epithelial membrane antigen were added for nonseminomas. In embryonal carcinoma, c-kit reacted in 17 of 22 cases, OCT3/4 in 18 of 22, and PLAP in 13 of 22. OCT3/4 was superior to PLAP in intensity and percent cells staining. In seminoma, OCT3/4 and D2-40 were superior to PLAP in intensity and percent cells; c-kit and AP-2gamma were superior in percent cells. D2-40 stained 23 of 24 seminomas strongly but had only weak focal reactivity in 6 of 17 embryonal carcinomas. Sensitivity and specificity were high for OCT3/4 discriminating seminoma and embryonal carcinoma, and c-kit discriminating seminoma, from other germ cell tumors. For embryonal carcinoma, OCT3/4 had higher specificity (0.94) than CD30 (0.786) owing to CD30 reactivity in 3 of 10 teratomas. Epithelial membrane antigen discriminated teratoma from other nonseminomas with a sensitivity of 1 but reacted occasionally in embryonal carcinoma (3/15) and yolk sac tumor (2/7). In conclusion, for extragonadal seminoma, OCT3/4, AP-2gamma, D2-40, and c-kit were equivalently superior to PLAP. For embryonal carcinoma, OCT3/4 was superior to PLAP and more specific than CD30. D2-40 is recommended to discriminate between seminoma and embryonal carcinoma.