Human kidney injury molecule-1 (hKIM-1) is a type 1 transmembrane protein that is not detectable in normal kidney tissue but is expressed at high levels in human and rodent kidneys with dedifferentiated proximal tubule epithelial cells after ischemic or toxic injury. Therefore, it was hypothesized that renal tumors express hKIM-1 and release this protein into the urine. Forty renal cell carcinoma (RCC) and 484 nonrenal tumors were analyzed by immunohistochemistry for expression of hKIM-1 (group 1). Urine samples before nephrectomy and nephrectomy tissue samples were collected from an additional 42 patients with renal tumors, from 30 normal control subjects, and also from 10 patients with prostate carcinoma (group 2). In five additional patients with RCC, urine was collected before and after nephrectomy (group 3). Tissue was examined for expression of hKIM-1, and cell-free urine supernatants were analyzed for hKIM-1 by ELISA. Urinary hKIM-1 was normalized to the urinary creatinine concentration (U Cr ). Expression of hKIM-1 was present in 32 tissue sections (91%) of 35 clear cell RCC (group 1). In group 2, the normalized urinary hKIM-1 levels were significantly higher in patients with clear cell RCC (0.39 ؎ 0.08 ng/mg U Cr ; n ؍ 21), compared with levels in patients with prostate carcinoma (0.12 ؎ 0.03 ng/mg U Cr ; P < 0.02; n ؍ 10), or normal control subjects (0.05 ؎ 0.01 ng/mg U Cr ; P < 0.005; n ؍ 30). Tissue sections from 28 (82%) of 34 primary RCC stained positively for the expression of hKIM-1. In all patients with a detectable prenephrectomy urinary hKIM-1 level, there was either complete disappearance or marked reduction after nephrectomy (group 3). In conclusion, the cleaved ectodomain of hKIM-1 can be detected in the urine of patients with RCC and may serve as a new biomarker for early detection of RCC.
Overall, our understanding of preeclampsia has developed significantly and the future holds promise for mechanism-based novel diagnostics and therapeutics.
Abstract-Activating angiotensin II type 1 autoantibodies (AT1-AAs) develop in women with preeclampsia and may contribute to the disorder. Insulin resistance and serum concentrations of the antiangiogenic soluble fms-like tyrosine kinase 1 (sFlt-1) are also increased in women with preeclampsia compared with normal pregnancy. sFlt-1 and insulin resistance decrease substantially after delivery; however, significant group differences persist postpartum. Women who have had preeclampsia are at increased cardiovascular risk later in life. We measured AT1-AAs in groups of women with previous preeclampsia (nϭ29) and previous normal pregnancies (nϭ35) 18Ϯ9 months after the first completed pregnancy. These women had had sFlt-1, insulin resistance homeostasis model assessment score, and related cardiovascular risk factors measured. Activating antibodies were detected by the chronotropic response of cultured neonatal rat cardiomyocytes coupled with receptor-specific antagonists (losartan and prazosin). AT1-AAs were detected in 17.2% of women with previous preeclampsia versus 2.9% of women with previous uncomplicated pregnancies (PϽ0.05). In contrast, there was no difference in the prevalence of autoantibodies against the ␣1-adrenoceptor (10% of previous preeclamptic versus 14% of previous normal pregnant). Women with activating autoantibodies had significantly increased sFlt-1, reduced free vascular endothelial growth factor, and higher insulin resistance homeostasis model assessment values compared with autoantibody-negative women. These data suggest that, as with sFlt-1 and insulin resistance, the AT1-AA does not regress completely after delivery and, secondarily, that correlations exist among these variables. The impact of AT1-AA after preeclampsia, especially in the context of cardiovascular risk, remains to be determined. Key Words: angiotensin II Ⅲ autoantibodies Ⅲ preeclampsia Ⅲ pregnancy Ⅲ soluble vascular endothelial growth factor receptor-1 Ⅲ insulin resistance Ⅲ cardiovascular disease P reeclampsia is a devastating complication of pregnancy featuring proteinuria and hypertension that commences after 20 weeks of gestation. The condition affects 5% of pregnancies in the United States and Europe and represents a major cause of fetal and maternal morbidity and mortality. 1 The cause of preeclampsia is unknown; however, evidence is accumulating that the disorder results from poor placentation combined with underlying maternal constitutional factors, such as insulin resistance, obesity, and inflammation, that become accentuated during the physiological stress of pregnancy. 1-3 Although the preeclampsia syndrome remits within days after delivery, women with a history of preeclampsia have a substantially higher cardiovascular risk later in life compared with women who experienced normal pregnancies. 2,4 -6 Wallukat et al 7 showed that women with preeclampsia develop circulating angiotensin II type 1 (AT1) autoantibodies (AT1-AAs) that bind an amino acid sequence of the second extracellular loop of the angiotensin II typ...
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