Renal Lithium Clearance Research Articles

Treating Bipolar Disorder in Older Adults Tricky, but Manageable

Treating Bipolar Disorder in Older Adults Tricky, but Manageable

Effect of acetazolamide on lithium reabsorption and lithium-induced GSK3β phosphorylation in rat kidney.

Lithium promotes the phosphorylation of glycogen synthase kinase-3β (GSK3β), and this reaction protects against acute kidney injury mediated by renal apoptosis. Lithium is considered to be reabsorbed by sodium-phosphate cotransporters and sodium-proton exchanger NHE3. This study evaluated the relation between the lithium reabsorption and the phosphorylation of GSK3β, by using acetazolamide, an NHE3 inhibitor. In rats infused with lithium chloride, the plasma concentration of lithium was 4.77 mEq/l, and the renal clearance of lithium and its fractional excretion were calculated to be 2.29 ml/min/kg and 0.405, respectively. Coadministration of acetazolamide decreased creatinine clearance and the reabsorption rate of lithium, increased the fractional excretion of lithium, and did not affect its plasma concentration. Western blot analysis exhibited the facilitation of GSK3β phosphorylation in the kidney cortex by lithium infusion, and acetazolamide inhibited the lithium-induced phosphorylation of GSK3β. Lithium did not affect GSK3β phosphorylation in the liver and did not affect Akt in the kidney cortex and liver. These data show that lithium reabsorption contributes to GSK3β phosphorylation in the kidney cortex.

Effect of renal ischemia on urinary excretion of lithium in rats.

Lithium, administered to patients with bipolar disorders, is mainly excreted in the urine, and tubular reabsorption is involved. This study characterized the renal excretion of lithium in rats subjected to renal ischemia for 60min or 90min. After intravenous injection of lithium chloride at 25mg/kg, the pharmacokinetic parameters of lithium were determined. In sham-operated rats, the renal clearance of lithium was calculated to be 1.49ml/min/kg, and its ratio to creatinine clearance (fractional excretion) was 43.4%. Renal ischemia inhibited the renal excretion of lithium, and did not affect its fractional excretion. The urinary pH of rats with renal ischemia for 90min was significantly higher than those of the other groups, and the linear regression with the fractional excretion of lithium in rats with renal ischemia showed a moderate correlation (r=0.650, p=0.00193). This study demonstrated the effect of renal ischemia on the renal excretion of lithium in rats. It was suggested that not only glomerular filtration but also the reabsorption of lithium was impaired by renal ischemia.

Nonlinear disposition of lithium in rats and saturation of its tubular reabsorption by the sodium-phosphate cotransporter as a cause.

We previously reported the contribution of sodium-phosphate cotransporter to the tubular reabsorption of lithium in rats. In the present study, the dose dependency of the renal handling of lithium was examined in rats. When lithium chloride at 1.25mg/kg, 2.5mg/kg and 25mg/kg was intravenously injected as a bolus, the areas under the plasma concentration-time curve of lithium until 60minutes were calculated to be 6.23mEq·min/l, 8.77mEq·min/l and 64.6mEq·min/l, respectively. The renal clearance of lithium and its fractional excretion increased with increments in the dose administered. The renal clearance of lithium strongly correlated with the urinary excretion rate of phosphate in the 1.25mg/kg group (r = 0.840) and 2.5mg/kg group (r = 0.773), whereas this correlation was weak in the 25mg/kg group (r = 0.306). The infusion of foscarnet, a typical inhibitor of sodium-phosphate cotransporter, decreased the fractional reabsorption of lithium in rats administered lithium chloride at 2.5mg/kg, but did not affect it in rats administered 25mg/kg. These results demonstrate the nonlinearity of the renal excretion of lithium in rats, with the saturation of lithium reabsorption by the sodium-phosphate cotransporter potentially being involved.

Enantioselective Effect of Flurbiprofen on Lithium Disposition in Rats

Aims: Lithium is administered for treating bipolar disorders and is mainly excreted into urine. Nonsteroidal anti-inflammatory drugs inhibit this process. In this study, we examined the enantioselective effect of flurbiprofen on the disposition of lithium in rats. Methods: Pharmacokinetic experiments with lithium were performed. Results: Until 60 min after the intravenous administration of lithium chloride at 30 mg/kg as a bolus, 17.8% of lithium injected was recovered into the urine. Its renal clearance was calculated to be 1.62 mL/min/kg. Neither creatinine clearance (C_cr) nor pharmacokinetics of lithium was affected by the simultaneous injection of (R)-flurbiprofen at 20 mg/kg. (S)-flurbiprofen impaired the renal function and interfered with the urinary excretion of lithium. The ratio of renal clearance of lithium to C_cr was decreased by the (S)-enantiomer. Conclusion: This study clarified that the (S)-flurbiprofen but not (R)-flurbiprofen inhibited the renal excretion of lithium in rats.

Foscarnet, an inhibitor of the sodium-phosphate cotransporter NaPi-IIa, inhibits phosphorylation of glycogen synthase kinase-3β by lithium in the rat kidney cortex

Lithium, which is used in the treatment of and prophylaxis for bipolar disease, inhibits glycogen synthase kinase-3β (GSK3β) by producing its phosphorylated form (p-GSK3β). GSK3β plays a role in apoptosis and some kinds of acute kidney injuries, and the formation of p-GSK3β is considered to contribute to protection against acute kidney injury. We previously reported that the sodium-phosphate cotransporter NaPi-IIa (SLC34A1) mediated the reabsorption of lithium in the rat kidney. In the present study, the phosphorylation status of GSK3β in the kidney cortex of rats administered lithium chloride and foscarnet, a typical inhibitor of NaPi-IIa, was examined using Western blotting. Under a 2-h infusion of lithium chloride, the plasma concentration of lithium was 1.06 mEq/l, and its renal clearance was calculated as 1.18 ml/min/kg, which was 29.6% of creatinine clearance. The abundance of p-GSK3β in the kidney cortex was augmented by the administration of lithium. The simultaneous infusion of foscarnet increased the renal clearance of lithium and its ratio to creatinine clearance as well as the urinary excretion of phosphate. Foscarnet also inhibited the lithium-induced phosphorylation of GSK3β. These results suggest that the reabsorption of lithium by NaPi-IIa triggers the phosphorylation of GSK3β in the rat kidney cortex.

Sodium-phosphate cotransporter mediates reabsorption of lithium in rat kidney

Lithium, used for the treatment of bipolar disorders, is reabsorbed via sodium-transport system in the proximal tubule. This step causes intra-/inter-individual difference of lithium disposition, and it has not been unclear which transporter contributes. In this study, we examined effect of foscarnet and parathyroid hormone (PTH), inactivators for sodium-phosphate cotransporter, and phlorizin, a typical inhibitor for sodium-glucose cotransporter, on the disposition of lithium in rats. Their intravenous administration stimulated urinary excretion of phosphate or glucose. After the intravenous injection of lithium chloride as a bolus, plasma concentration of lithium decreased time-dependently. The renal clearance of lithium was calculated to be 0.740ml/min/kg in control rats, and this was 26.7% of creatinine clearance. Foscarnet and PTH significantly increased the renal clearance of lithium and its ratio to creatinine clearance, suggesting that they prevented the reabsorption of lithium. No effect of phlorizin on the renal handling of lithium was recognized. In control rats, the renal clearance of lithium showed a strong correlation with the renal excretion rate of phosphate, compared with creatinine clearance. These findings suggest that sodium-phosphate cotransporter reabsorbs lithium in the rat kidney. Furthermore, its contribution was estimated to be more than 65.9% in the lithium reabsorption. And, this study raised the possibility that therapeutic outcome of lithium is related with the functional expression of sodium-phosphate cotransporter in the kidney.

Lithium Toxicity in the Setting of Nonsteroidal Anti-Inflammatory Medications

Lithium toxicity is known to affect multiple organ systems, including the central nervous system. Lithium levels have been used in the diagnosis of toxicity and in assessing response to management. There is evidence that nonsteroidal anti-inflammatory medications (NSAIDs) can increase lithium levels and decrease renal lithium clearance. We present a case of lithium toxicity, which demonstrates this effect and also highlights the fact that lithium levels do not correlate with clinical improvement, especially the neurological deficit.

Enhanced renal Na+reabsorption by carbohydrate in beverages during restitution from thermal and exercise-induced dehydration in men

We examined whether carbohydrate in beverages accelerated fluid retention during recovery from thermal and exercise-induced dehydration and whether it was caused in part by an enhanced renal Na+ reabsorption rate due to insulin secretion. After dehydrating by ∼2.3% body weight by exercise in a hot environment, seven young men underwent high-carbohydrate, low-carbohydrate, or control rehydration trials by drinking one of three beverages with 3.4 g glucose + 3.1 g fructose, 1.7 g glucose + 1.6 g fructose, or 0.0 g glucose + 0.0 g fructose per deciliter, respectively, in a common composition of electrolyte solution: 21 meq/l [Na+], 5 meq/l [K+], 16.5 meq/l [Cl-], 10 meq/l [citrate(-3)]. They drank the same amount of beverage as total body weight loss within 30 min. During the 60 min before the start of drinking and the following 180 min, we measured plasma volume (PV), plasma glucose ([Glc]p), serum insulin ([Ins]s), plasma Na+ concentrations, and the renal clearances of inulin, lithium, and Na+ with plasma vasopressin ([AVP]p) and aldosterone concentrations ([Ald]p) every 30 min. After dehydration, PV decreased by ∼5% and plasma osmolality increased by ∼6 mosmol/kg H2O in all trials with no significant differences among them. We found in the high-carbohydrate trial that 1) PV increased faster than in the control trial and remained at the higher level than other trials for the last 60 min (P < 0.05); 2) accumulated urine volume was smallest after 90 min (P < 0.05); 3) the renal Na+ reabsorption rate was greatest for the first 120 min (P < 0.05); 4) during which period [AVP]p and [Ald](p) were not significantly different from other trials (both, P > 0.9); and 5) [Glc](p) and [Ins]s were highest from 45 to 105 min (P < 0.05) during rehydration. Thus carbohydrate in beverages enhances renal Na+ reabsorption, and insulin is possibly involved in this enhancement.

The Effects of Syzygium aromaticum-Derived Oleanolic Acid on Kidney Function of Male Sprague–Dawley Rats and on Kidney and Liver Cell Lines

Studies indicate that Syzygium spp-derived oleanolic acid (OA) enhances renal function of streptozotocin (STZ)-induced diabetic rats as evidenced by its reversal of the previously reported inability of the kidney to excrete Na+ in these animals. We postulated that OA influences Na+ excretion in the proximal tubule, the site where two-thirds of filtered NaCl is reabsorbed through a process mediated by transport proteins. Therefore, the study investigated the effects of OA on proximal tubular Na+ handling in male Sprague–Dawley rats using renal lithium clearance (CLi). Renal CLi has been used widely in animal and clinical studies to assess proximal tubular function. Sub-chronic doses of OA were administered to rats twice every third day for 5 weeks. Rats treated with deionized water served as control animals. Cytotoxicity of OA on kidney and liver cell lines was assessed by the MTT and comet assays. OA increased Na+ excretion of conscious male Sprague–Dawley rats from week 3 to week 5. By the end of the 5-week experimental period, OA treatment significantly reduced (p < 0.05) plasma creatinine concentration of STZ-induced diabetic rats with a concomitant elevation in glomerular filtration rate (GFR). Acute OA infusion was also associated with increases in fractional excretion of sodium (FENa) and lithium (FELi) in anesthetized rats in the absence of significant changes in GFR. The MTT assay studies demonstrated that OA increased the metabolic activity of kidney and liver cell lines. Taken together with previous observations, this study implicates the proximal tubule in OA-evoked increases in urinary Na+ output.

Erythropoietin down‐regulates proximal renal tubular reabsorption and causes a fall in glomerular filtration rate in humans

Recombinant human erythropoietin (rHuEPO) elevates haemoglobin concentration both by increasing red blood cell volume and by a decrease in plasma volume. This study delineates the association of rHuEPO-induced changes in blood volumes with changes in the renin–aldosterone system and renal function. Sixteen healthy males were given rHuEPO for 28 days in doses raising the haematocrit to 48.3±4.1%.Renal clearance studieswith urine collections (N = 8) were done at baseline and at days 4, 11, 29 and 42. Glomerular filtration rate (GFR) was measured by 51Cr-EDTA.Renal clearance of lithium (CLi)was used as an index of proximal tubular outflow and to assess segmental renal tubular handling of sodium and water. rHuEPO-induced increases in haematocrit occurred from day 10 onwards and was caused by both an increase in red cell volume and a fall in plasma volume. Well before that (from day 2 and throughout the treatment time), rHuEPO decreased plasma levels of renin and aldosterone (N = 8) by 21–33% (P < 0.05) and 15–36% (P < 0.05), respectively. After cessation of rHuEPO, values returned to baseline. On days 11 and 29, CLi increased (P < 0.02) indicating a significant 10–16% decrease in absolute proximal reabsorption of sodium and water (APR = GFR − CLi, P < 0.05). GFR decreased slightly, albeit significantly, on day 4 (P < 0.05). In conclusion, rHuEPO promptly, and before any changes in blood volumes and haematocrit can be detected, causes a down-regulation of the renin–aldosterone system. The results are compatible with a rHuEPO-induced reduction in proximal reabsorption rate leading to activation of the tubuloglomerular feedback mechanism and a fall in GFR. Therefore, treatment with rHuEPO may result in suppression of endogenous EPO synthesis secondary to a decrease in intrarenal oxygen consumption.

Lithium: Updated Human Knowledge Using an Evidence-Based Approach

After a single dose, lithium, usually given as carbonate, reaches a peak plasma concentration at 1.0-2.0 hours for standard-release dosage forms, and 4-5 hours for sustained-release forms. Its bioavailability is 80-100%, its total clearance 10-40 mL/min and its elimination half-life is 18-36 hours. Use of the sustained-release formulation results in 30-50% reductions in peak plasma concentrations without major changes in the area under the plasma concentration curve. Lithium distribution to the brain, evaluated using 7Li magnetic resonance spectroscopy, showed brain concentrations to be approximately half those in serum, occasionally increasing to 75-80%. Brain concentrations were weakly correlated with serum concentrations. Lithium is almost exclusively excreted via the kidney as a free ion and lithium clearance is considered to decrease with aging. No gender- or race-related differences in kinetics have been demonstrated. Renal insufficiency is associated with a considerable reduction in renal clearance of lithium and is considered a contraindication to its use, especially if a sodium-poor diet is required. During the last months of pregnancy, lithium clearance increases by 30-50% as a result of an increase in glomerular filtration rate. Lithium also passes freely from maternal plasma into breast milk. Numerous kinetic interactions have been described for lithium, usually involving a decrease in the drug's clearance and therefore increasing its potential toxicity. Clinical pharmacology studies performed in healthy volunteers have investigated a possible effect of lithium on cognitive functions. Most of these studies reported a slight, negative effect on vigilance, alertness, learning and short-term memory after long-term administration only. Because of the narrow therapeutic range of lithium, therapeutic monitoring is the basis for optimal use and administration of this drug. Lithium dosages should be adjusted on the basis of the serum concentration drawn (optimally) 12 hours after the last dose. In patients receiving once-daily administration, the serum concentration at 24 hours should serve as the control value. The efficacy of lithium is clearly dose-dependent and reliably correlates with serum concentrations. It is now generally accepted that concentrations should be maintained between 0.6 and 0.8 mmol/L, although some authors still favour 0.8-1.2 mmol/L. With sustained-release preparations, and because of the later peak of serum lithium concentration, it is advised to keep serum concentrations within the upper range (0.8-1 mmol/L), rather than 0.6-0.8 mmol/L for standard formulations. It is controversial whether a reduced concentration is required in elderly people. The usual maintenance daily dose is 25-35 mmol (lithium carbonate 925-1300 mg) for patients aged <40 years; 20-25 mmol (740-925 mg) for those aged 40-60 years; and 15-20 mmol (550-740 mg) for patients aged >60 years. The initial recommended dose is usually 12-24 mmol (450-900 mg) per day, depending on age and bodyweight. The classical administration schedule is two or three times daily, although there is no strong evidence in favour of a three-times-daily schedule, and compliance with the midday dose is questionable. With a modern sustained-release preparation, the twice-daily schedule is well established, although one single evening dose is being recommended by a number of expert panels.

Lithium use in special populations

Byline: E. Mohandas, V. Rajmohan Lithium, a monovalent cation, was first used for the treatment of mania in the 1940s. Half a century into its use, the drug continues to be the preeminent choice for bipolar disorder with antimanic, antidepressant (modest) and antisuicidal property. Lithium is the "gold standard" mood stabilizer against which potential mood stabilizer agents are judged. The therapeutic uses of lithium also include use as an augmenting agent in depression, schizoaffective disorder, aggression, impulse control disorder, eating disorders, attention deficit disorder and in certain subsets of alcoholism. Lithium has been used in many medical disorders, especially cluster headache and dermatological disorders (seborrheic dermatitis, eczematoid dermatitis, genital herpes).[sup] [1] The drug is however associated with neurologic, endocrine, cardiovascular, renal, dermatologic and gastrointestinal adverse effects and possible teratogenicity. History Lithium was first discovered and defined by Johan August Arfvedson in 1817 when he did an analysis of the mineral petalite [LiAl(Si2O5)2]. Petalite was first found by Brazilian scientist Jose Bonifacio Andrade e Silva in 1800. Lepidolite, spodumene, petalite and amblygonite are the more important minerals containing lithium. It was Arfwedson's laboratory chief John Jacob Berzelius who named this alkali metal "lithion." Arfvedson was never able to fully isolate lithium, and it wasn't until 1855 that it was isolated by William Thomas Brande. Brande and Sir Humphrey Davy earlier had done electrolysis on lithium oxide in 1818. Lithium was first produced commercially in 1923 by Metallgesellschaft AG.[sup] [2] The use of lithium for medicinal purposes can be traced back 1,800 years to the Greek physician Galen, who treated patients with mania by having them bathe in alkaline springs and drink the water, which probably contained lithium. In 1843 Alexander Ure introduced lithium into modern medicine, and he showed the in vitro reduction of weight of a uric acid bladder stone in a lithium carbonate solution. Sir Alfred Garrod later discovered that gouty uric acid deposits also were soluble in lithium solution. The view in that time was that uric acid imbalances caused a wide range of diseases, and Armand Trousseau and Alexander Haig proposed that mania and depression also may result from this imbalance and lithium may be effective in these conditions. In the 1840s, lithium was mixed with carbonate or citrate to form a salt and was used to treat gout, epilepsy, diabetes, cancer and insomnia. In the 1870s, the then American Surgeon General William Hammond had provided anecdotal evidence for the use of lithium bromide in the treatment of acute mania. In the 1880s and 1890s the Lange brothers Carl and Fritz used lithium in depression, and Carl Lange was the first to systematically use lithium in the acute and prophylactic treatment of depression.[sup] [2] The introduction of lithium preparations and tablets in the 1900s brought to the fore the toxic effects of the drug; and there were reports of weakness, tremor, diarrhea, vomiting and deaths. The drug disappeared from the British Pharmacopoeia by 1932, but later in the 1940s it was used as a sodium substitute in low sodium diets; but the reports of severe intoxication led to its removal from American markets in 1949. [sup] [1] The appearance in 1949 in the Medical Journal of Australia of a paper entitled "Lithium salts in the treatment of psychotic excitement" by John F. J. Cade was an unspectacular entry into a new era of psychiatry. Manic patients showed improvement, with the patient becoming calmer after four to five days. There was no improvement in the excited schizophrenic patients, though there was a calming effect. There was no improvement or deepening of depression. The paper also gave details of initial dosage, maintenance doses, appearance of toxic symptoms and warning about lithium over-dosage. …

Lithium Poisoning

The clinical features and pharmacokinetics of 22 lithium overdoses are described. Effectiveness of different treatment regimens regarding elimination of lithium is discussed. Origin of overdose was due to deliberate poisoning or precipitated by concomitant diseases, coadministration of drugs, or combination of both. Treatment included supportive care, diuretics (15/22), hemodialysis (HD; 9/22), and mechanical ventilation (3/22). Severity of lithium intoxication was classified in 50% as I degrees, in 41% as II degrees, and in 9% as III degrees according to Hansen and Amdisen. Renal impairment on admission was diagnosed in 82% of the patients. Half-life of lithium in serum was 3.5 +/- 0.8 hours during the first HD, and 29 +/- 14 and 29 +/- 6 hours during therapy with diuretics or supportive treatment, respectively. Lithium clearance during HD was 160 +/- 15 mL/min, and renal clearance during HD or treatment with diuretics was approximately 20 and 15 +/- 9 mL/min, respectively. Renal lithium clearance was not influenced by HD therapy. There was no difference regarding half-life and clearance between the group that had an unspecific treatment or the group treated with diuretics. Hemodialysis is the therapy of choice for emergent extracorporeal lithium elimination. Renal impairment and interaction with other drugs were the main reasons for intoxication; thus, more cautious prescription or more frequent supervision of this patient group is warranted. It seems that treatment with diuretics does not have a beneficial effect in the overdose setting.

Secondary Mania in Older Adults

Although mania is commonly associated with bipolar disorder, it can have many etiologies (1). Thus, “primary mania” results from bipolar disorder, whereas “secondary mania” results from pharmacological, metabolic, or neurologic causes (1, 2). Older adults are at risk for secondary mania because of increased medical comorbidities and neurological changes. In one retrospective study of 50 patients with mania who were older than 65 years, it was the first manic episode for 28% of the patients and 71% had a comorbid neurological disorder (3). The etiology of mania is important because although acute symptomatic treatment of both primary and secondary mania may be similar, appropriate treatment of secondary mania includes addressing the cause (1). We present here two case histories of secondary mania in older adults, discuss their presentations and differential diagnosis in turn, and discuss treatment.

Loss of Tubuloglomerular Feedback in Decompensated Liver Cirrhosis: Physiopathological Implications

In healthy subjects, arterial pressure reduction or renal ischemia produces renal artery dilatation through autoregulation and tubuloglomerular feedback (TuGF). Patients with decompensated cirrhosis have reduced kidney perfusion pressure but show renal vasoconstriction instead of autoregulation-mediated vasodilation. This study investigates the consequences of kidney autoregulation loss on renal perfusion, glomerular filtration rate, and tubular handling of electrolytes in both compensated and ascitic nonazotemic cirrhotic patients. Forty-two consecutive patients with diuretic-free liver cirrhosis (32 with preascitic and 10 with ascitic disease) and 10 controls were submitted to the following determinations: (a) basal plasma renin activity and aldosterone levels; (b) endogenous dopaminergic activity measured as incremental aldosterone responses during metoclopramide administration; and (c) renal clearances of sodium, potassium, inulin, para-aminohippurate and lithium. Compared with the other groups, ascitic patients showed lower renal plasma flow (P < 0.01) and lithium clearance (P < 0.05), a higher filtration fraction (P < 0.01), and secondary aldosteronism. Controls and preascitic patients displayed tubuloglomerular feedback (the mechanism increasing the glomerular filtration rate when a reduced sodium load reaches the distal tubule), as demonstrated by negative correlations between fractional excretion of lithium (an expression of fractional delivery of sodium to the distal nephron) and glomerular filtration rate (respectively, r = -0.73, P < 0.03, and r = -0.48, P < 0.01). Conversely, patients with ascites showed a positive correlation between lithium fractional excretion and glomerular filtration rate (r = 0.64, P < 0.05). Reduction in renal perfusion, increased filtration fraction, and TuGF derangement, as found in decompensated patients, are indicative of prevalent postglomerular arteriolar vasoconstriction, with ensuing stimulation of proximal tubular sodium reabsorption.

Evidence of a dynamic aldosterone‐independent distal tubular control of renal sodium excretion in compensated liver cirrhosis*

In preascitic cirrhosis increased sodium retention occurs in kidney distal tubule in spite of normal aldosterone plasma levels. No clearance technique can dissect the respective contribution to sodium retention exerted by Henle's loop, distal convoluted tubule and collecting duct, so we evaluated proximal and distal tubular sodium handling in preascites during two manoeuvres that temporarily increase aldosterone secretion. Ten patients with compensated cirrhosis and nine controls were studied in recumbency, during standing and after dopamine receptor blockade with metoclopramide through: 4 h renal clearances of sodium, potassium, lithium and creatinine; plasma levels of active renin and aldosterone. Whilst comparable in recumbency, aldosterone levels significantly rose during standing and after metoclopramide in both groups. In patients, dopaminergic blockade caused a fall of distal sodium delivery (P < 0.01) but urinary sodium excretion was unchanged because the reabsorbed fraction of distal sodium delivery also fell (P < 0.03). Cirrhotic patients showed the same findings in the passage from recumbency to standing. In preascitic cirrhosis, the distal tubular segments of the nephron are able to cope with decreases in tubular flow by reducing reabsorption at an aldosterone-independent site (possibly the loop of Henle).

Systemic nitric oxide production and renal function in nonazotemic human cirrhosis: a reappraisal

OBJECTIVES: Several studies in human cirrhosis have demonstrated increased nitric oxide (NO) production. In experimental animals, intracerebroventricular administration of NO donors causes a marked depression of the endogenous dopaminergic activity, a function known to be physiologically recruited and exerting a natriuretic function in patients with compensated cirrhosis. The aim of this study is to evaluate the interaction between the systemic plasma levels of NO, the endogenous dopaminergic activity and the main parameters of renal function in patients with liver cirrhosis of differing degrees of severity. METHODS: A total of 21 patients (11 with preascitic and 10 with nonazotemic diuretic-free ascitic cirrhosis) and 10 healthy control subjects underwent the following tests: a) basal plasma renin activity (PRA) and aldosterone levels; b) renal clearances of sodium, potassium, inulin, para-minohippurate and lithium (the latter being a measure of the fluid delivery to the distal nephron); c) NO systemic plasma levels measured through paramagnetic resonance spectroscopy as nitrosylhemoglobin complexes; d) endogenous dopaminergic activity, evaluated by means of the incremental prolactin and aldosterone plasma levels after dopaminergic blockade with i.v. metoclopramide. RESULTS: NO plasma values and endogenous dopaminergic activity, although significantly increased with respect to healthy controls, were not different in the two groups of patients. The plasma NO/PRA ratio was significantly higher in the group of compensated patients with respect to ascitic cirrhotics (respectively, 18.3 ± 11.8 vs 3.5 ± 2.6 A.U./ng/ml/h, p < 0.001). Compared with compensated cirrhotics, patients with ascites showed significantly lower values of glomerular filtration rate (GFR) and renal plasma flow (RPF). Interestingly, GFR values were substantially the same in the ascitic patients and the control subjects. Compensated patients displayed a significant positive correlation between metoclopramide-induced incremental aldosterone plasma levels ( i.e., endogenous dopaminergic tone) and fractional excretion of sodium ( r = 0.58; p < 0.05). In the group of compensated patients, NO levels correlated inversely with creatinine plasma concentrations ( r = −0.85; p < 0.001) and directly with inulin clearance ( r = 0.65; p < 0.05). CONCLUSIONS: These data show that, at least in compensated cirrhotic patients, the stimulation of systemic NO production and the increased dopaminergic function may be mechanisms preventing renal perfusion, GFR, and fractional excretion of sodium from precocious reductions.

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.

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.