Proteinuria Precedes Cerebral Edema in Stroke-Prone Rats

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Abstract
Background and Purpose —Stroke-prone spontaneously hypertensive rats (SHRSP) subjected to high sodium intake develop severe hypertension, cerebral edema, and proteinuria, culminating in organ damage and early death. MRI, which can be applied serially, provides the unique opportunity to study temporal and quantitative relations between these changes and whether diminution of sodium intake can attenuate established cerebral edema. Methods —SHRSP were subjected to 1% NaCl in drinking water. Cerebral MRI, proteinuria and systolic blood pressure (SBP) were measured serially. After detection of cerebral edema (T2-weighted MRI), 6 rats were killed for histology, to confirm the diagnosis of cerebral edema. The others were followed up for 7 more days while salt loading was continued (n=10, group 1) or after sodium intake was normalized (n=7, group 2). Results —SHRSP invariably developed cerebral edema in 30 days (range, 8 to 54 days). At this point neurological signs were absent in 16 of 23 rats. SBP rose until 1 week before detection of cerebral edema, and then stabilized at approximately 265 mm Hg. Proteinuria invariably preceded cerebral edema, with a concentration exceeding 40 mg/d predicting development of cerebral edema in 9 days (range, 3 to 15 days). There was linear correlation ( R =.62, P <.0001) between proteinuria and cerebral edema (pixels with an intensity above a defined threshold). Rats in group 1 showed an increase in cerebral edema (from 5.8±1.1% to 12.5±2.8%; P <.05), and proteinuria remained high (from 305±44 to 338±29 mg/d); and 2 died spontaneously. Rats in group 2 showed no significant change in edema (from 4.9±0.5% to 6.9±1.3%) but a marked fall in proteinuria (from 294±24 to 119±10 mg/d; P <.05), both significantly different from group 1 ( P <.05); all survived. SBP remained unaltered in both groups. Conclusions —Our data establish MRI as a sensitive method for detection of cerebral edema, often prior to neurological signs, in SHRSP. Proteinuria predicts cerebral edema, and these two variables, both obtained noninvasively, are quantitatively related. Moreover, in SHRSP normalizing sodium intake after salt loading attenuates development of cerebral edema and reduces proteinuria.