THE CRITICAL BP THRESHOLD DEPENDENCE OF HYPERTENSIVE INJURY AND REPAIR IN A MALIGNANT NEPHROSCLEROSIS MODEL

Most patients with essential hypertension do not exhibit substantial renal damage. Renal autoregulation, by preventing glomerular transmission of systemic pressures has been postulated to mediate this resistance. Conversely, malignant nephrosclerosis (MN) has been postulated to develop when severe hypertension exceeds a critical ceiling. If the concept is valid, even modest BP reductions to below this threshold regardless of antihypertensive class (i) should prevent MN and (ii) lead to the healing of the already developed MN lesions. Both predicates were tested using BP radiotelemetry in the stroke prone spontaneously hypertensive rats (SHRsp) receiving 1% NaCl as drinking fluid for 4 weeks. Severe hypertension (final 2 weeks average systolic BP, >200 mmHg) and MN (histologic damage score 36±5; n=27), developed in the untreated SHRsp but were prevented by all antihypertensive classes [enalapril (n=15), amlodipine (n=13) or a hydralazine/hydrochlorothiazide combination (n=15)], if the final 2 week systolic BP remained <190mmHg. More impressively, modest systolic BP reductions to 160–180mmHg (Hydralazine/Hydrochlorothiazide regimen) initiated at ∼4 wks in additional untreated rats after MN had already developed (injury score 35±4 in the right kidney removed before therapy) led to a striking resolution of the vascular and glomerular MN injury over 2–3 weeks (post therapy left kidney injury score 9±2, p<0.0001; n=27). Proteinuria also declined rapidly from 122±9.5 mg/24 hr before therapy to 20.5±3.6mg 1 week later. These data clearly demonstrate the barotrauma mediated pathogenesis of MN and the striking capacity for spontaneous and rapid repair of hypertensive kidney damage if new injury is prevented.