Refractory Ascites: Modulation of Atrial Natriuretic Factor Unresponsiveness by Mannitol

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Abstract
We have previously shown that unresponsiveness to atrial natriuretic factor is a marker of the severity of ascites. The tubular mechanisms are unknown, but it seems that increased reabsorption of sodium proximal to the main site of action of atrial natriuretic factor (i.e., the inner medullary collecting duct) plays an important role. We attempted to decrease the proximal reabsorption of sodium with mannitol in patients unresponsive to atrial natriuretic factor. The results of mannitol in such a group of patients has previously been conflicting. We studied 10 patients with massive, resistant ascites who were off diuretics and on a 20–mmol/day sodium diet for 7 days. Atrial natriuretic factor unresponsiveness was confirmed by failure of a 2–hr atrial natriuretic factor infusion to induce a natriuresis. The next day all patients received an infusion of 40 gm of mannitol and subsequently a combined infusion of mannitol and atrial natriuretic factor. Proximal reabsorption of sodium and water were evaluated by lithium clearance, and glomerular filtration rate and renal blood flow were evaluated by inulin clearance and p–aminohippurate clearances, respectively. Six patients responded to mannitol alone with an increased diuresis (from 39 ± 7 to 148 ± 35 ml/hr) and natriuresis (from 0.27 ± 0.05 mmol/hr to 1.65 ± 0.53 mmol/hr; p < 0.05) (responders), whereas four did not (nonresponders). The combination of atrial natriuretic factor and mannitol induced a further significant increase in sodium excretion (3.28 ± 0.68 mmol/hr) but not in urine excretion, compared with mannitol alone. Lithium clearance increased in the responders after mannitol infusion, but it did not increase further with ANF plus mannitol. Inulin and p–aminohippurate clearances were equally low in the two groups and did not change during the infusions. The responders had significantly lower plasma renin activity, aldosterone and norepinephrine levels than the nonresponders (plasma renin activity = 1.9 ± 0.7 vs. 7.3 ± 1.5 ng/L/sec; aldosterone = 2,830 ± 1,273 vs. 9,457 ± 3,873 pmol/L; norepinephrine = 2.6 ± 1.6 vs. 8.4 ± 1.6 nmol/L; p < 0.05). We conclude the following: (a) atrial natriuretic factor unresponsiveness in cirrhotic patients is due, in part, to increased reabsorption of sodium proximal to the distal site of atrial natriuretic factor action; (b) increased proximal reabsorption of sodium might be mediated in part by increased renin aldosterone and sympathetic nervous system activity; with moderate as opposed to marked elevation, this effect can be overcome by mannitol; and (c) with increased mannitol–induced distal delivery of sodium, atrial natriuretic factor further increases sodium excretion, indicating that receptor or intracellular signaling of atrial natriuretic factor response remains intact. (Hepatology 1992;16:42-48.)