Cimetidine administration and tubular creatinine secretion in patients with compensated cirrhosis.

Cimetidine inhibits the tubular secretion of creatinine, without altering the glomerular filtration rate (GFR). During cimetidine administration the creatinine/inulin clearance ratio approaches unity in patients with renal failure. We determined the clearance of lithium (an index of fluid delivery to the distal nephron), inulin (a measure of the actual GFR) and creatinine during cimetidine administration to investigate the occurrence of tubular creatinine secretion in patients with compensated cirrhosis. A total of 12 patients with Child-Pugh A cirrhosis were studied initially. The subjects consumed a stable diet containing 100 mmol of sodium. On successive days, 9 h creatinine clearances were measured, first without and then with the oral administration of cimetidine (400 mg as a priming dose, followed by 200 mg every 3 h). During the first study day, 4 h renal lithium clearance was also calculated. A further group of five patients with fully compensated cirrhosis underwent the measurement (on successive days) of plasma inulin clearance, first without and then with the oral administration of cimetidine (same schedule of drug administration). Cimetidine administration unmasked a marked overestimation of GFR when calculated as creatinine clearance (baseline, 138+/-20 ml/min; +cimetidine, 89+/-13 ml/min; P<0.01). Consequently, during cimetidine administration the calculated lithium fractional excretion (a measure of the fraction of filtered sodium load that is delivered to the loop of Henle) rose from 21.4+/-13.2% to 32.3+/-18.9% (P<0.05), and the ratio between absolute distal tubular sodium reabsorption and filtered sodium load rose from 20.6+/-13.1% to 31.6+/-19.3% (P<0.01). Cimetidine caused no significant decrease in the actual GFR (i.e. inulin clearance) when administered to the second group of patients with compensated cirrhosis. Our data demonstrate significant tubular secretion of creatinine in patients with compensated cirrhosis and, consequently, a marked overestimation of GFR and filtered sodium load and an underestimation of the fractional distal tubular sodium reabsorption when these parameters are calculated by means of the traditional creatinine and lithium clearance computation. The true GFR (measured as inulin clearance) is unaffected by cimetidine administration.

Dopaminergic control of renal tubular function in patients with compensated cirrhosis.

In normal humans, plasma dopamine levels rise during head-out water immersion or saline intravenous infusion. Dopamine inhibits Na+,K+-ATPase activity in the proximal tubule and blunts aldosterone secretion leading to increased diuresis and natriuresis. The aim of this study is to evaluate the role of endogenous dopaminergic activity in the intrarenal sodium handling in patients with compensated liver cirrhosis. We studied nine healthy controls and 12 patients with Child-Pugh A cirrhosis during a normosodic diet for (1) dopaminergic activity, as measured by the incremental aldosterone responses 30 and 60 min after intravenous metoclopramide administration; (2) basal plasma levels of active renin and aldosterone; (3) 4-hr renal clearance of lithium (an index of fluid delivery to the distal tubule), creatinine, sodium, and potassium, first without and then with dopaminergic blockade with intravenous metoclopramide. The patients displayed greater endogenous dopaminergic activity, evidenced by higher incremental aldosterone responses compared with controls (+30 min: 160.2 +/- 68.8 vs 83.6 +/- 35.2 pg/ml, P < 0.01; +60 min: 140.5 +/- 80.3 vs 36.8 +/- 39.1 pg/ml, P < 0.01, respectively). In spite of this, patients and controls did not show significantly different basal aldosterone plasma levels, delivery of sodium to the distal nephron, or urinary excretion of sodium. In both groups the dopaminergic blockade with metoclopramide determined no change in sodium and potassium urinary excretion, but it caused a fall of the fluid and sodium delivery from the proximal tubule to the distal nephron among the patients (from 30.7 +/- 9.3 to 14.4 +/- 4.5 ml/min, P < 0.001; and from 4.25 +/- 1.30 to 2.00 +/- 0.64 meq/min, P < 0.001, respectively). In this group the natriuresis was maintained due to a reduction of the reabsorbed fraction of the distal sodium delivery (from 97.5 +/- 1.9% to 89.8 +/- 12.4%, P < 0.05). In conclusions, compensated cirrhotic patients display an increased endogenous dopaminergic activity compared with controls. This function is critical in maintaining the delivery of sodium to the distal nephron.