Lithium Clearance Research Articles

Segmental Regulation of Sodium and Water Excretion by TRPV1 Activation in the Kidney

Our previous studies show that activation of the transient receptor potential vanilloid type 1 (TRPV1) channels by a selective agonist, capsaicin (CAP), given unilaterally into the renal pelvis leads to increases in urine flow rate (Uflow) and urinary sodium excretion (UNa) bilaterally, although the mechanisms underlying enhanced renal excretory function are unknown. The present study was designed to determine the contribution of each of the renal segments to enhanced renal excretory function when TRPV1 expressed in sensory nerve fibers innervating the renal pelvis is activated. To accomplish the goal, LiCl was given intravenously to male Wistar rats while the left renal pelvis (LRP) was perfused with vehicle or CAP with or without a selective TRPV1 antagonist, capsazepine (CAPZ). Uflow and clearance of creatinine, lithium, sodium, and water, either filtered or fractionally, were determined in both kidneys. LRP perfusion of CAP at 2.4 nmol increased Uflow (microL.ming; ipsilaterally from 6.6 +/- 0.6 to 14.6 +/- 2.2 and contralaterally from 7.4 +/- 0.7 to 13.9 +/- 1.8, P < 0.05) and UNa (micromol.ming; ipsilaterally from 0.6 +/- 0.2 to 1.8 +/- 0.3 and contralaterally from 0.7 +/- 0.2 to 1.9 +/- 0.4, P < 0.05). Ipsilateral blockade of the TRPV1 with CAPZ at 24 nmol prevented CAP-induced increases in Uflow and UNa bilaterally. Creatinine, lithium, sodium, and free water clearance (ml.min) were increased in CAP (1.47 +/- 0.27, 0.44 +/- 0.05, 0.026 +/- 0.004, 0.41 +/- 0.05, respectively) compared to vehicle (0.72 +/- 0.12, 0.25 +/- 0.05, 0.010 +/- 0.001, 0.24 +/- 0.05), CAPZ+CAP (0.83 +/- 0.13, 0.24 +/- 0.03, 0.014 +/- 0.002, 0.23 +/- 0.03), and CAPZ (0.88 +/- 0.05, 0.21 +/- 0.01, 0.010 +/- 0.001, 0.20 +/- 0.01) groups (P <or= 0.01). Filtered sodium load, distal delivery of sodium, and distal sodium reabsorption (muEq.min) were also increased in CAP (202.2 +/- 33.3, 61.3 +/- 7.4, 57.6 +/- 7.4, respectively) compared to vehicle (97.7 +/- 16.6, 33.6 +/- 5.8, 32.2 +/- 5.9), CAPZ+CAP (110.5 +/- 16.3, 32.5 +/- 4.5, 30.7 +/- 4.3), and CAPZ (118.0 +/- 4.5, 27.9 +/- 1.2, 26.8 +/- 1.2) groups (P <or= 0.01). In contrast, fractional lithium and sodium excretion, absolute proximal reabsorption, fractional proximal reabsorption, fractional distal sodium, and water reabsorption were not different among groups. Therefore, activation of the TRPV1 expressed in primary afferent nerves innervating the renal pelvis leads to diuresis and natriuresis in both kidneys. The TRPV1-induced sodium and water excretion appears to be mediated by increases in glomerular filtration rate and distal tubular delivery of sodium but not by suppression of renal proximal and distal tubular reabsorption, suggesting a key role of segmental regulation of renal function by TRPV1-positive primary sensory nerves in the maintenance of sodium and water homeostasis.

Blood Pressure and Renal Sodium Handling in Relation to Genetic Variation in the DRD1 Promoter and GRK4

Activation of type-1 dopamine receptors (DRD1) reduces renal sodium reabsorption. In a family-based random sample of 611 untreated whites (women, 45.0%; mean age, 38.6 years), we measured blood pressure (BP). We used the endogenous lithium clearance to assess fractional sodium excretion (FE(Na)) and proximal (RNa(prox)) and distal (RNa(dist)) tubular sodium reabsorption. We investigated multivariate-adjusted associations with the DRD1 promoter (A-48G, G-94A, and C-800T) and GRK4 (Ala142Val). The frequent DRD1 haplotypes were AGC (48.2%), GGT (34.4%), and AAC (14.3%). While standardizing to mean sodium excretion (8.7 mmol/h) and adjusting for covariates and relatedness, RNa(dist) was lower in DRD1 -94GG homozygotes than -94A allele carriers (effect size, -0.94%; P=0.005) with opposite findings for FE(Na) (+0.084%; P=0.014). AGC carriers (-0.88%; P=0.012) and AAC carriers (+1.00%; P=0.004) had different RNa(dist) compared to corresponding noncarriers. Furthermore, FE(Na) was lower in AAC carriers than in noncarriers (-0.082%; P=0.019). The family-based analyses identified a significant between-family component in the variance of the renal phenotypes associated with the DRD1 polymorphisms. Transmission of the DRD1 AGC haplotype was also associated with lower systolic (-3.54 mm Hg; P=0.016) and diastolic (-2.80 mm Hg; P=0.0064) BPs without significant between-family variance component. Plasma renin activity and urinary aldosterone excretion were not associated with DRD1 variation. The GRK4 Ala142Val polymorphism did not contribute to the phenotypes under study. In conclusion, renal sodium handling and BP were associated with genetic variation in the DRD1 promoter. The between-family variance component excluded population stratification for BP, but not for the renal phenotypes.

A new accurate method for predicting lithium clearance and daily dosage requirements in adult psychiatric patients

The present study aimed to derive new equations for estimating lithium clearance and daily dosage requirements needed to achieve an intended lithium serum level for adult psychiatric inpatients and outpatients. Data were retrospectively collected from 60 adult psychiatric patients (34 males and 26 females, aged between 18-80 years) in both inpatient and outpatient settings. All variables that might affect lithium clearance and/or lithium serum concentration were included and analyzed by stepwise multiple linear regression to produce equations describing lithium clearance and daily dosage requirements for these patients. The validation of the developed equations was performed by application to another 60 psychiatric subjects in both the inpatient and outpatient settings. The bias and accuracy of the new methods were also compared to those set forth by the empirical method and the a priori methods developed by Zetin, Pepin, Jermain and Terao and colleagues. The following prediction equations for lithium clearance (CL(Li)) were obtained: CL(Li) (inpatients) = 0.932 + 0.185CL(Cr) and CL(Li) (outpatients) = 1.021 + 0.141CL(Cr). The equations derived for daily dosage requirements were: daily dose (inpatients, mg) = 350.15 + 289.92 (desired lithium level, mmol/L) + 0.84 (weight, kg) - 1.76 (age, years) + 34.43 [tricyclic antidepressant (TCA), yes = 1, no = 0] + 62.1(CL(Cr), L/h) + 13.1 [blood urea nitrogen (BUN), mmol/L] + 40.9 (sex, male = 1, female = 0) and daily dose (outpatients, mg) = 784.92 + 530.22 (desired lithium level, mmol/L) + 8.61 (weight, kg) - 12.09 (age, years) - 11.14 (TCA, yes = 1, no = 0) - 7.63 (CL(Cr), L/h) - 42.62 (BUN, mmol/L) - 23.43 (sex, male = 1, female = 0). In the present method, the prediction error for clearance was 10.31% and 6.62% for inpatients and outpatients, respectively, and the prediction error for daily dosage requirements was 3.96% and 2.95% for inpatients and outpatients, respectively. Compared to previously reported methods, the present method proved to be accurate and can be safely used for the prediction of lithium clearance and daily dosage requirements in psychiatric inpatients and outpatients.

Inhibition of mineralocorticoid receptors with eplerenone alleviates short-term cyclosporin A nephrotoxicity in conscious rats

Recent data indicate that aldosterone aggravates cyclosporin A (CsA)-induced nephrotoxicity. We examined whether the mineralocorticoid receptor (MR) blocker eplerenone (EPL) antagonized early deterioration of renal function and blood pressure (BP) increase in CsA-treated rats. Male Sprague-Dawley rats received CsA (15 mg/kg/day i.p.) and/or EPL (100 mg/kg/day p.o.) for 21 days. After 2 weeks, arterial, venous and urinary bladder catheters were implanted and the rats were trained to accept a restraining device allowing arterial blood sampling and direct measurement of BP and renal function. BP was measured on-line in conscious rats. CsA significantly increased systolic BP: 139 +/- 4 versus 134 +/- 2 mmHg, reduced body weight gain: -5 +/- 6 versus 36 +/- 7 g, glomerular filtration rate (GFR): 1.02 +/- 0.16 versus 2.64 +/- 0.27 ml/min, renal blood flow (RBF): 5.3 +/- 2.4 versus 13.5 +/- 2.1 ml/min and lithium clearance (C(Li+)): 0.16 +/- 0.04 versus 0.26 +/- 0.07 ml/min compared to controls. These changes were prevented by simultaneous EPL treatment: systolic BP, 130 +/- 4 mmHg; weight gain, 53 +/- 7 g; GFR, 1.67 +/- 0.26 ml/min; RBF, 12.3 +/- 2.1 ml/min and C(Li+), 0.27 +/- 0.03 ml/min. Analysis of kidney morphology after the CsA treatment showed hyaline vacuolization in tubules and vascular depositions in arterioles; these changes were less pronounced after combination therapy. No significant changes were seen regarding haemoglobin, haematocrit, plasma renin and vasopressin, plasma and urinary sodium, potassium, or osmolality. MR blockade by EPL prevented short-term alterations in GFR, RBF and hypertension associated with CsA nephrotoxicity. We conclude that the aldosterone-MR pathway contributes markedly to the renal toxicity induced by this calcineurin inhibitor.

Renal effects of urodilatin in healthy subjects are independent of blockade of the cyclooxygenase and angiotensin II receptor

Objective. Little is known about the role of the renin–angiotensin–aldosterone system and the renal prostaglandins in modulating the renal vasoconstrictive and natriuretic effects of synthetic urodilatin (URO) in healthy humans. Material and methods. Twelve volunteers were pretreated in a randomized, single‐blind, crossover study with losartan 50 mg a day or placebo for 5 days. Another 12 healthy subjects received indomethacin 25 mg three times a day or placebo for 4 days and a single dose on day 5. All subjects received a URO infusion (15 ng kg−1 min−1) on day 5. Radioactive tracers and the lithium clearance technique were used. Results. The effective renal plasma flow (ERPF) decreased significantly during URO infusion: losartan pretreatment 573±63 to 461±76 mL/min versus placebo 540±89 to 432±90 mL/min. The urinary sodium excretion rate (UNa) increased significantly during URO infusion: losartan 335±115 to 502±134 umol/min (micromol/min) (UNa) versus placebo 386±142 to 476±137 umol/min (micromol/min) (UNa). In the indomethacin pretreated subjects, ERPF decreased significantly from 530±109 to 446±55 mL/min versus 533±89 to 449±69 mL/min in the placebo group. UNa increased significantly from 395±142 to 768±254 umol/min (micromol/min) (UNa) in the indomethacin group versus 282±117 to 552±242 umol/min (micromol/min) (UNa) in placebo. Conclusion. The renal vasoconstrictive and natriuretic effects of synthetic URO are not modified by sustained inhibition of the angiotensin II receptor or the cyclooxygenase in man in a sodium replete state.

Dipeptidyl peptidase IV inhibition downregulates Na+-H+exchanger NHE3 in rat renal proximal tubule

In the microvillar microdomain of the kidney brush border, sodium hydrogen exchanger type 3 (NHE3) exists in physical complexes with the serine protease dipeptidyl peptidase IV (DPPIV). The purpose of this study was to explore the functional relationship between NHE3 and DPPIV in the intact proximal tubule in vivo. To this end, male Wistar rats were treated with an injection of the reversible DPPIV inhibitor Lys [Z(NO2)]-pyrrolidide (I40; 60 mg.kg(-1).day(-1) ip) for 7 days. Rats injected with equal amounts of the noninhibitory compound Lys[Z(NO2)]-OH served as controls. Na(+) - H(+) exchange activity in isolated microvillar membrane vesicles was 45 +/- 5% decreased in rats treated with I40. Membrane fractionation studies using isopycnic centrifugation revealed that I40 provoked redistribution of NHE3 along with a small fraction of DPPIV from the apical enriched microvillar membranes to the intermicrovillar microdomain of the brush border. I40 significantly increased urine output (67 +/- 9%; P < 0.01), fractional sodium excretion (63 +/- 7%; P < 0.01), as well as lithium clearance (81 +/- 9%; P < 0.01), an index of end-proximal tubule delivery. Although not significant, a tendency toward decreased blood pressure and plasma pH/HCO(3)(-) was noted in I40-treated rats. These findings indicate that inhibition of DPPIV catalytic activity is associated with inhibition of NHE3-mediated NaHCO3 reabsorption in rat renal proximal tubule. Inhibition of apical Na(+) - H(+) exchange is due to reduced abundance of NHE3 protein in the microvillar microdomain of the kidney brush border. Moreover, this study demonstrates a physiologically significant interaction between NHE3 and DPPIV in the intact proximal tubule in vivo.

Terlipressin improves renal function in patients with cirrhosis and ascites without hepatorenal syndrome

Patients with advanced cirrhosis and ascites are characterized by circulatory dysfunction with splanchnic vasodilatation and renal vasoconstriction, which often lead to ascites. The vasoconstrictor terlipressin improves renal function in hepatorenal syndrome (HRS). The aim of this study was to evaluate if terlipressin also improves renal function in patients with ascites without HRS. Twenty-three patients with cirrhosis participated; 15 with nonrefractory ascites were randomized to either terlipressin (N group, n = 11) or a placebo (P group, n = 4), and 8 had refractory ascites and received terlipressin (R group). The glomerular filtration rate (GFR), sodium clearance (C(Na)), lithium clearance (C(Li)), osmolal clearance (C(Osm)), and urine sodium concentration (U(Na)) were assessed before and after the injection of 2 mg of terlipressin or the placebo. GFR increased in the N group (69 +/- 19 versus 92 +/- 25 mL/min, P < 0.005) and in the R group (31 +/- 19 versus 41 +/- 31 mL/min, P < 0.05) after terlipressin. In the N group, terlipressin induced an increase in C(Na) (0.89 +/- 0.21 versus 1.52 +/- 1.45 mL/min, P < 0.05), C(Li) (17.3 +/- 8.9 versus 21.5 +/- 11.6 mL/min, P < 0.05), and C(Osm) (2.10 +/- 0.81 versus 3.06 +/- 2.0 mL/min, P < 0.05). In the R group, terlipressin induced an increase in C(Na) (0.11 +/- 0.18 versus 0.35 +/- 0.40 mL/min, P < 0.05) and C(Li) (5.5 +/- 4.2 versus 9.5 +/- 8.55 mL/min, P < 0.05). U(Na) increased in both groups after terlipressin (P < 0.005). Plasma norepinephrine (P < 0.05) and renin (P < 0.05) decreased after terlipressin. All parameters remained unchanged after the placebo. The vasopressin 1 receptor agonist terlipressin improves renal function and induces natriuresis in patients with cirrhosis and ascites without HRS. Vasoconstrictors may represent a novel future treatment modality for these patients.

Conceptual Basis and Methodology of the SOPHIA Study

To clarify the role of gene polymorphisms on the effect of losartan and losartan plus hydrochlorothiazide on blood pressure (primary end point) and on cardiac, vascular and metabolic phenotypes (secondary end point) after 4, 8, 12, 16 and 48 weeks treatment, an Italian collaborative study - The Study of the Pharmacogenomics in Italian hypertensive patients treated with the Angiotensin receptor blocker losartan (SOPHIA) - on never-treated essential hypertensives (n = 800) was planned. After an 8 week run-in, losartan 50 mg once daily will be given and doubled to 100 mg at week +4 if blood pressure is more than 140/90 mmHg. Hydroclorothiazide 25 mg once daily at week +8 and amlodipine 5 mg at week +16 will be added if blood pressure is more than 140/90 mmHg. Cardiac mass (echocardiography), carotid intima-media thickness, 24 h ambulatory blood pressure, homeostatic model assessment (HOMA) index, microalbuminuria, plasma renin activity and aldosterone, endogenous lithium clearance, brain natriuretic peptide and losartan metabolites will be evaluated. Genes of the renin-angiotensin-aldosterone system, salt sensitivity, the beta-adrenergic system and losartan metabolism will be studied (Illumina custom arrays). A whole-genome scan will also be performed in half of the study cohort (1M array, Illumina 500 GX beadstation).

Renal expression of parvalbumin is critical for NaCl handling and response to diuretics

The distal convoluted tubule (DCT) plays an essential role in the reabsorption of NaCl by the kidney, a process that can be inhibited by thiazide diuretics. Parvalbumin (PV), a Ca(2+)-binding protein that plays a role in muscle fibers and neurons, is selectively expressed in the DCT, where its role remains unknown. We therefore investigated the renal phenotype of PV knockout mice (Pvalb(-/-)) vs. wild-type (Pvalb(+/+)) littermates. PV colocalized with the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC) in the early DCT. The Pvalb(-/-) mice showed increased diuresis and kaliuresis at baseline with higher aldosterone levels and lower lithium clearance. Acute furosemide administration increased diuresis and natriuresis/kaliuresis, but, surprisingly, did not increase calciuria in Pvalb(-/-) mice. NaCl supplementation of Pvalb(-/-) mice increased calciuria at baseline and after furosemide. The Pvalb(-/-) mice showed no significant diuretic response to hydrochlorothiazide, but an accentuated hypocalciuria. A decreased expression of NCC was detected in the early DCT of Pvalb(-/-) kidneys in the absence of ultrastructural and apoptotic changes. The PV-deficient mice had a positive Ca(2+) balance and increased bone mineral density. Studies in mouse DCT cells showed that endogenous NCC expression is Ca(2+)-dependent and can be modulated by the levels of PV expression. These results suggest that PV regulates the expression of NCC by modulating intracellular Ca(2+) signaling in response to ATP in DCT cells. They also provide insights into the Ca(2+)-sparing action of thiazides and the pathophysiology of distal tubulopathies.

Haemodynamic and renal effects of endothelin receptor antagonism in patients with chronic kidney disease

Endothelin-1 (ET-1) has been implicated in the pathophysiology of chronic kidney disease (CKD) and ET receptor blockade has shown renoprotective effects in animals. We examined the haemodynamic and renal effects of an ET receptor antagonist, TAK-044, in patients with CKD. Seven patients with CKD (mean arterial pressure 103 mmHg; mean plasma creatinine 3.5 mg/dl) received three 15 min intravenous infusions, each separated by at least 7 days, of either placebo or TAK-044 (100 or 750 mg) in a randomized, double blind crossover study. Systemic and renal haemodynamics, and plasma immunoreactive ET-1, big ET-1 and C-terminal fragment concentrations, were determined before and after the infusions of placebo and drugs. Compared with placebo, TAK-044 reduced mean arterial pressure (MAP) (100 mg: 7.4 +/- 1.9 mmHg, 750 mg: 8.4 +/- 2.3 mmHg, P < 0.01) and systemic vascular resistance index (100 mg: 650 +/- 140 dyne.s.cm(-5).m(-2), 750 mg: 829 +/- 141 dyne.s.cm(-5).m(-2), P < 0.01) at both doses. TAK-044 increased cardiac index and heart rate to a similar degree at both doses. With regards to renal haemodynamics, TAK-044 had no significant effect on the glomerular filtration rate at either dose but tended to increase renal plasma flow (100 mg: 9.6 +/- 5.0 ml/min, 750 mg: 25.3 +/- 19.5 ml/min) and decreased the effective filtration fraction (100 mg: 3.6 +/- 1.1%, 750 mg: 4.7 +/- 1.7%, P < 0.01), in a dose-dependent manner. TAK-044 had no significant effect on sodium or lithium clearance, or on fractional excretion of sodium and lithium. Plasma ET-1 concentrations rose more than two-fold after 750 mg TAK-044 while big ET-1 and C-terminal fragment concentrations were unchanged. These findings suggest an important role for ET-1 in controlling systemic and renal haemodynamics in patients with CKD. The antihypertensive and potentially renoprotective actions of ET receptor antagonists shown in this study may prove useful in slowing the progression of CKD. Clinical trials are now needed to address these key questions for CKD.

P1,P4-Diadenosine Tetraphosphate (Ap4A) Inhibits Proximal Tubular Reabsorption of Sodium in Rats

Background/Aims: P¹,P⁴-diadenosine tetraphosphate (Ap₄A) is a vasoactive dinucleotide possessing natriuretic activity. It is unclear, however, which part of the nephron is the target site of action for Ap₄A. Methods: We evaluated the tubular sites of Ap₄A action using the lithium clearance technique. Results: Ap₄A at a priming dose of 2 µmol/kg with subsequent infusion at 20 nmol/kg/min increased fractional water and sodium excretion 2.5- and 5.6-fold, respectively. Moreover, Ap₄A increased lithium clearance 1.9-fold and fractional lithium excretion 2.8-fold. Fractional water and sodium excretion from distal nephron segments was not significantly affected by Ap₄A. Conclusion: These results suggest that Ap₄A induces natriuresis mainly through inhibition of proximal tubular reabsorption of sodium.

Context Dependency of Serum and Urinary Lithium: Implications for Measurement of Proximal Sodium Reabsorption

To the Editor: As reported previously in this journal, the endogenous lithium clearance is a marker of proximal tubular sodium handling.1,2 To investigate the context dependency of the endogenous lithium clearance, we measured by electrothermal atomic absorption spectrophotometry the lithium concentrations in serum and in exactly timed urine samples in 745 whites (51.5% women) and …

CYP3A5 and ABCB1 Genes Influence Blood Pressure and Response to Treatment, and Their Effect Is Modified by Salt

The permeability-glycoprotein efflux-transporter encoded by the multidrug resistance 1 (ABCB1) gene and the cytochromes P450 3A4/5 encoded by the CYP3A4/5 genes are known to interact in the transport and metabolism of many drugs. Recent data have shown that the CYP3A5 genotypes influence blood pressure and that permeability-glycoprotein activity might influence the activity of the renin-angiotensin system. Hence, these 2 genes may contribute to blood pressure regulation in humans. We analyzed the association of variants of the ABCB1 and CYP3A5 genes with ambulatory blood pressure, plasma renin activity, plasma aldosterone, endogenous lithium clearance, and blood pressure response to treatment in 72 families (373 individuals; 55% women; mean age: 46 years) of East African descent. The ABCB1 and CYP3A5 genes interact with urinary sodium excretion in their effect on ambulatory blood pressure (daytime systolic: P=0.05; nighttime systolic and diastolic: P<0.01), suggesting a gene-gene-environment interaction. The combined action of these genes is also associated with postproximal tubular sodium reabsorption, plasma renin activity, plasma aldosterone, and with an altered blood pressure response to the angiotensin-converting enzyme inhibitor lisinopril (P<0.05). This is the first reported association of the ABCB1 gene with blood pressure in humans and demonstration that genes encoding for proteins metabolizing and transporting drugs and endogenous substrates contribute to blood pressure regulation.

Renal sodium handling in patients with normal pressure glaucoma

Low BP (blood pressure) is a recognized risk factor for some patients with NPG (normal pressure glaucoma). We have shown previously that patients with orthostasis have impaired circadian renal handling of sodium, which may contribute to the low BP. Therefore the aim of the present study was to examine the renal handling of sodium, the circadian variations in BP and the neurohormonal response to an orthostatic test in a selected subpopulation of 18 patients with NPG with vasospastic and orthostatic symptoms, and in 24 healthy control subjects. The variations in BP and renal tubular sodium handling were evaluated using 24 h ambulatory BP recordings, 24 h urine collections and determination of endogenous lithium clearance as a marker of proximal sodium reabsorption. The neurohormonal and BP responses to changes in posture were also determined in a 30 min orthostatic test. This selected group of patients with NPG had lower 24 h ambulatory BPs (P<0.001), and a more pronounced fall in BP when assuming an upright position (P<0.001) compared with controls. FE(Li) (fractional excretion of lithium) was higher in patients with NPG than controls during the day (36.6+/-21.8 compared with 20.4+/-8.7% respectively; P<0.01; values are means+/-S.D.) as well as during the night (38.8+/-41.9 compared with 19.7+/-10.8% respectively; P<0.02), suggesting a reduced reabsorption of sodium in the proximal tubule. This was compensated for by an increased distal reabsorption of sodium in patients with NPG (P<0.01). These data demonstrate that patients with vasospastic NPG have a high excretion of lithium, suggesting reduced sodium reabsorption in the proximal tubule, in spite of a low BP. The abnormal renal sodium handling might contribute to the maintenance of arterial hypotension and progression of the optic nerve damage in these patients.

Servo-Control of Water and Sodium Homeostasis during Renal Clearance Measurements in Conscious Rats

Servo-controlled fluid and sodium replacement during clearance studies is used in order to prevent loss of body fluid and sodium following diuretic/natriuretic procedures. However, even under control conditions, the use of this technique is sometimes associated with increases in proximal tubular fluid output (assessed by lithium clearance) and excretion rates. The present study examined the reason for these increases. The first series of experiments showed that one cause is volume overloading. This can occur if the servo system is activated from the start, i.e., during the establishment of a suitably high urine flow rate by constant infusion of hypotonic glucose solution. The second series of experiments showed that replacement of blood samples with donor blood can also lead to increases in fractional lithium excretion and accompanying increases in water and sodium excretion, a problem not seen when blood samples are replaced with the animal’s own red blood cells resuspended in isotonic saline. When these pitfalls are avoided, servo-controlled sodium and fluid replacement is a reliable technique that makes it possible to study the effects of natriuretic and/or diuretic stimuli without interference from unwanted changes in extracellular volume.

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. …

Time course of the renal functional response to partial nephrectomy: measurements in conscious rats

Previous investigations into the functional responses of the surviving nephrons following reductions in renal mass have been performed largely in anaesthetized animals and have taken little account of how the compensatory changes develop with time. The present study has assessed a method for determining glomerular filtration rate (GFR) in unrestrained, uncatheterized, conscious rats (plasma disappearance of (99m)Tc-diethylenetriamene pentaacetic acid (DTPA)) and has used this method to document the time course of the changes in GFR over a 32 day period following uninephrectomy or 5/6 nephrectomy. Concurrent measurements of excretion rates and of the clearance of lithium (the latter being an index of end-proximal fluid delivery) provided information on changes in overall tubular function and segmental reabsorption. After uninephrectomy, the GFR of the remaining kidney (compared with that of a single kidney of sham-operated animals) increased maximally (by approximately 50%) within 8 days; after 5/6 nephrectomy, the increase in the GFR of the remnant kidney was maximal (at approximately 300%) within 16 days. Overall excretion rates of sodium and potassium were well maintained in partially nephrectomized animals throughout the period of study, while the excretion of water increased (by approximately 30% after uninephrectomy and by approximately 120% after 5/6 nephrectomy), partly as a result of the compensatory increases in GFR but mainly as a consequence of moderate (after uninephrectomy) or marked (after 5/6 nephrectomy) reductions in fractional reabsorption. During the early period after 5/6 nephrectomy, potassium excretion sometimes exceeded the filtered load, indicating net secretion. Lithium clearance data indicated that the changes in tubular function after 5/6 nephrectomy include a reduction in fractional reabsorption in the proximal tubule, whereas after uninephrectomy any such effect on the proximal tubule is minor and transient.

Combined Effects of Carbonic Anhydrase Inhibitor and Adenosine A1 Receptor Antagonist on Hemodynamic and Tubular Function in the Kidney

Background: Carbonic anhydrase inhibitors (CAI) reduce proximal reabsorption, activating tubuloglomerular feedback (TGF) and reducing glomerular filtration rate (GFR). Adenosine A₁ receptors (A₁R) mediate the TGF response and stimulate proximal reabsorption. Methods: Clearance and micropuncture studies were performed in Wistar rats to determine whether blockade of A₁R (KW3902 0.3 mg/kg i.v.) would prevent CAI (benzolamide 5 mg/kg i.v.) from lowering GFR, whether CAI and KW3902 exert additive effects on sodium excretion, and to what extent such interactions depend on events in the glomerulus, proximal tubule, or distal nephron. Results: KW3902 raised GFR and prevented CAI from lowering GFR. KW3902 and CAI caused additive diuresis and natriuresis. KW3902 and CAI increased lithium clearance, but their effects were redundant. CAI increased the dependence of proximal reabsorption on active chloride transport. KW3902, alone, did likewise, but to a lesser extent than CAI. Adding KW3902 to CAI lessened the shift toward active chloride transport. Conclusions: The data reveal that A₁R mediate glomerular vascular resistance whether or not TGF is activated, that additive effects of CAI and KW3902 on salt excretion occur, in part, because KW3902 inhibits reabsorption downstream from the macula densa, and that KW3902 likely inhibits proximal reabsorption by interfering with apical sodium-hydrogen exchange.

Acute growth hormone administration induces antidiuretic and antinatriuretic effects and increases phosphorylation of NKCC2

Growth hormone (GH) has antidiuretic and antinatriuretic effects in rats and humans, but the molecular mechanisms responsible for these effects are unknown. The aim of this study was to investigate the mechanisms behind the acute renal effects of GH in rats. Female rats received rat (r)GH (2.8 mg/kg sc) or saline and were placed in metabolic cages for 5 h. Urinary excretion of electrolytes and urinary volume were reduced after rGH injection, while urine osmolality was increased. Creatinine and lithium clearance remained unchanged, suggesting that rGH increases reabsorption in segments distal to the proximal tubule. Total plasma insulin-like growth factor I (IGF-I) levels did not change, while cortical IGF-I mRNA abundance was increased. The relative abundance of total and Ser(256)-phosphorylated aquaporin 2 was found to be unchanged by immunoblotting, whereas a significant increase of Thr(96) and Thr(101)-phosphorylated NKCC2 (renal Na(+), K(+), 2Cl(-) cotransporter) was found in the inner stripe of outer medulla thick ascending limbs (mTAL). Additionally, an increased NKCC2 expression was observed in the cortical region. Immunohistochemistry confirmed these findings. The density of NKCC2 molecules in the apical membrane of mTAL cells appeared to be unchanged after rGH injection evaluated by immunoelectron microscopy. Basolateral addition of rGH or IGF-I to microperfused rat mTAL segments did not change transepithelial voltage. In conclusion, GH appears to exert its acute antinatriuretic and antidiuretic effects through indirect activation of NKCC2 in the mTAL.

Association Between Arterial Properties and Renal Sodium Handling in a General Population

Mean arterial pressure drives pressure-natriuresis and determines arterial structure and function. In a population sample, we investigated the relation between arterial characteristics and renal sodium handling as assessed by the clearance of endogenous lithium. We ultrasonographically measured diameter, cross-sectional compliance (CC) and distensibility (DC) of the carotid, brachial, and femoral arteries in 1069 untreated subjects (mean age: 41.6 years; 50.1% women; 18.8% hypertensive subjects). While accounting for covariates and standardizing for the sodium excretion rate in both sexes, CC and DC of the femoral artery increased with higher fractional distal sodium reabsorption. Differences associated with a 1-SD change in fractional distal reabsorption of sodium were 51.7 mm(2)/kPax10(-3) (95% CI: 23.9 to 79.5; P=0.0002) and 0.56x10(-3)/kPa (95% CI: 0.17 to 0.94; P=0.004) for femoral CC and DC, respectively. In women as well as in men, a 1-SD increment in fractional proximal sodium reabsorption was associated with decreases in femoral and brachial diameter, amounting to 111.6 mum (95% CI: 38.2 to 185.1; P=0.003) and 52.5 mum (95% CI: 10.0 to 94.9; P=0.016), respectively. There was no consistent association between the properties of the elastic carotid artery and renal sodium handling. In conclusion, higher fractional sodium reabsorption in the distal nephron is associated with higher femoral CC and DC, and higher proximal sodium reabsorption is associated with decreased brachial and femoral diameters. These findings demonstrate that there might be an influence of renal sodium handling on arterial properties or vice versa or that common mechanisms might influence both arterial and renal function.