Abstract-Angiogenesis inhibition is an established treatment for several tumor types. Unfortunately, this therapy is associated with adverse effects, including hypertension and renal toxicity, referred to as "preeclampsia." Recently, we demonstrated in patients and in rats that the multitarget tyrosine kinase inhibitor sunitinib induces a rise in blood pressure (BP), renal dysfunction, and proteinuria associated with activation of the endothelin system. In the current study we investigated the effects of sunitinib on rat renal histology, including the resemblance with preeclampsia, as well as the roles of endothelin 1, decreased nitric oxide (NO) bioavailability, and increased oxidative stress in the development of sunitinib-induced hypertension and renal toxicity. In rats on sunitinib, light and electron microscopic examination revealed marked glomerular endotheliosis, a characteristic histological feature of preeclampsia, which was partly reversible after sunitinib discontinuation. The histological abnormalities were accompanied by an increase in urinary excretion of endothelin 1 and diminished NO metabolite excretion. In rats on sunitinib alone, BP increased (⌬BP: 31.6Ϯ0.9 mm Hg). This rise could largely be prevented with the endothelin receptor antagonist macitentan (⌬BP: 12.3Ϯ1.5 mm Hg) and only mildly with Tempol, a superoxide dismutase mimetic (⌬BP: 25.9Ϯ2.3 mm Hg). Both compounds could not prevent the sunitinib-induced rise in serum creatinine or renal histological abnormalities and had no effect on urine nitrates but decreased proteinuria and urinary endothelin 1 excretion. Our findings indicate that both the endothelin system and oxidative stress play important roles in the development of sunitinib-induced proteinuria and that the endothelin system rather than oxidative stress is important for the development of sunitinib-induced hypertension. (Hypertension. 2011;58:295-302.) • Online Data Supplement

Serum cystatin C is believed to reflect the glomerular filtration rate (GFR) more closely than serum creatinine in many contexts and a reference interval for serum cystatin C in term pregnancy has been defined to enable its use also in pregnant women. However, serum cystatin C levels were not found to be decreased in term pregnancy, though GFR of low molecular mass substances is known to increase by at least 40% by the third trimester. The aim of this study was therefore to determine whether serum cystatin C is a reliable GFR marker also in pregnant women. GFR was determined by measurement of plasma clearance of iohexol in 48 previously healthy women in their third trimester and in 12 healthy nonpregnant women, and was compared with their serum levels of cystatin C and creatinine. Both serum cystatin C and creatinine levels were significantly related to GFR for both pregnant and non-pregnant women. However, the correlation between cystatin C and GFR was set at different levels for pregnant and nonpregnant women. Our results indicate a physiological difference between the filtration processes in kidneys of pregnant and non-pregnant women, whether it is size-dependent, configuration-dependent or charge-dependent. Nevertheless, serum cystatin C seems to reflect GFR reliably in both non-pregnant and pregnant, healthy and hypertensive women.

Objective To investigate the proportion of women with findings characteristic for pre‐eclampsia, as opposed to renal disease, in a controlled study of hypertensive pregnant women undergoing antepartum renal biopsy. Design An observational prospective controlled study. Setting University Hospital of Lund, Sweden. Sample Thirty‐six previously healthy women with hypertensive disease in pregnancy, consecutively admitted to the antenatal ward at onset of disease during a 20 month period and giving informed consent, as well as 12 voluntary healthy pregnant controls. Methods Renal biopsy samples were obtained from all participants and evaluated by light microscopy, electron microscopy and immunofluorescence techniques. Main outcome measures Presence and degree of glomerular endotheliosis. Results Glomerular endotheliosis was present in all women with pre‐eclampsia and gestational hypertension, and in 5 of the 12 controls, although significant differences in the degree of endotheliosis were found between the groups. Clinically undetected renal disease was not diagnosed in any of the women. Conclusion Glomerular endotheliosis was found in women with normal pregnancy as well as in both non‐proteinuric and proteinuric hypertension and is consequently not, as earlier believed, pathognomonic for pre‐eclampsia. The transition between normal term pregnancy, gestational hypertension and pre‐eclampsia appears to be a continuous process, perhaps of increasing adaptation to pregnancy. Pre‐eclampsia may be the extreme of the adaptational process, rather than a separate abnormal condition. Clinically undetected renal disease could be a rare cause of hypertension in pregnancy.

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The albumin levels decreased in the second and third trimesters, whereas the levels of chi2-macroglobulin were unchanged, which is compatible with a virtually unaltered transfer of chi2-macroglobulin between the intra- and extravascular space during pregnancy and a significantly increased extravascular fraction of albumin.