Low Creatininuria due to Hyponatremia Is Reversible in Many Patients

<b><i>Background:</i></b> Chronic hyponatremia has been reported to be associated with low solute intake and low creatinine excretion (reflecting likely sarcopenia). We wanted to study the effect, on the long term, of correction of hyponatremia on solute and creatinine excretion in chronic SIADH. <b><i>Methods:</i></b> We made a retrospective review of clinical and biochemical data of patients with euvolemic hyponatremia. We analyzed 24-h urine solute and creatinine excretion in volunteers with hyponatremia induced by dDAVP over 4 days, in 12 patients with chronic SIADH (&#x3e;1 month) before and after a few days of SNa correction and in 12 patients (6 women and 6 men) before and after 3 months of SNa correction by a vaptan or urea. <b><i>Results:</i></b> We confirm a low urine creatinine and solute excretion only in patients with chronic hyponatremia (&#x3e;1 month). Correction of SNa (from 127 ± 2.3 mEq/L to 139 ± 2.8 mEq/L) for &#x3e;3 months, in the 12 patients (mean age 58 ± 18), was associated with an increase in 24-h creatinine excretion (from 986 ± 239 to 1,238 ± 220 mg; <i>p</i> &#x3c; 0.02) and in patients treated with a vaptan (<i>n</i> = 5) solute excretion increased from 656 ± 207 mmol/24 h to 960 ± 193 mmol/24 h (<i>p</i> &#x3c; 0.02). Sodium excretion increased also in the 12 patients (from 100 ± 53 mEq/24 h to 169 ± 38 mEq/24 h; <i>p</i> &#x3c; 0.01). <b><i>Conclusion:</i></b> Chronic hyponatremia (&#x3e;1 month) is associated with a decrease in solute output (or intake) and in creatinine excretion. In many patients, these abnormalities are reversible in the long term.

MO130GLOMERULAR FILTRATION RATE IS THE MAIN PREDICTOR OF URINE OUTPUT IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD) PATIENTS TREATED WITH TOLVAPTAN

Background and Aims Tolvaptan was approved to treat autosomal dominant polycystic kidney disease (ADPKD) to slow the rate of kidney growth and renal function decline. Tolvaptan blocks the V2 vasopressin receptor in renal collecting ducts and distal nephron causing intense polyuria. Few authors have analyzed what factors influence the volume of diuresis in patients taking tolvaptan. Method We have analyzed the influence of solute excretion and glomerular filtration rate, besides age and gender as predictors of urine output, using multivariable analysis. In concret, we have searched the importance of osmolar excretion as predictor of volume of diuresis. Results We studied 24 h-urine samples from 18 ADPKD patients on treatment with tolvaptan, who had received the three doses: 45/15, 60/30 and 90/30 mg. Each patient was represented once per dose, for a total of 54 urine samples (Table 1). Tolvaptan increased urine volume, which was roughly doubled, and roughly halved urine solute concentrations expressed by volume and calculated osmolality. By contrast, solute concentrations expressed as ratios with creatinine remained constant as did osmolality corrected with urinary creatinine, indicating that there was no change in solute excretion after tolvaptan. Urine volume was correlated with serum creatinine (Rho= -0.36, p= 0.008), urinary creatinine (Rho = -0.29, p = 0.034) and GFR-MDRD4 (Rho = 0.44, p= 0.001). Urine volume was correlated with calculated daily osmolar excretion in Osm/day (Rho = 0.76, p &lt;0.001). Urine volume was not correlated with calculated urinary osmolality in mOsm/Kg (Rho= -0.04, p= 0.77) or as urinary osmolality/creatinine ratio (Rho= 0.23, p= 0.1). Correlation of urine volume with osmolar excretion was lost when urine volume was removed from the predictor variable. Urine volume was additionally not correlated with urinary urea o sodium concentrations nor their solute/creatinine ratios, and although it was correlated with urinary potassium concentration (Rho = -0.33, p=0.014), it was not correlated with potassium/creatinine ratio. We also performed a linear regression analysis searching predictors of urine volume. Only GFR and the osmolality/creatinine ratio were significant predictors of urine volume (urine volume= 55.35 x GFR + 4.74 x Osmolality/Cr; r2= 0.41, p&lt;0.001) but individual solute assessments or tolvaptan dose did not predict urine volume. Conclusions Therefore, urine volume after initiating tolvaptan in patients with ADPKD is influenced mainly by the degree of renal function. There might also be a contribution of urinary solute load but it can not be studied using total solute excretion due to collinearity. We propose that the urinary solute/creatinine ratio and osmolality/creatinine ratio should be used to search for predictors of urine output in patients on tolvaptan.

Sex differences in solute transport along the nephrons: effects of Na+ transport inhibition

Each day, ~1.7 kg of NaCl and 180 liters of water are reabsorbed by nephron segments in humans, with urinary excretion fine tuned to meet homeostatic requirements. These tasks are coordinated by a spectrum of renal Na+ transporters and channels. The goal of the present study was to investigate the extent to which inhibitors of transepithelial Na+ transport (TNa) along the nephron alter urinary solute excretion and how those effects may vary between male and female subjects. To accomplish that goal, we developed sex-specific multinephron models that represent detailed transcellular and paracellular transport processes along the nephrons of male and female rat kidneys. We simulated inhibition of Na+/H+ exchanger 3 (NHE3), bumetanide-sensitive Na+-K+-2Cl− cotransporter (NKCC2), Na+-Cl− cotransporter (NCC), and amiloride-sensitive epithelial Na+ channel (ENaC). NHE3 inhibition simulations predicted a substantially reduced proximal tubule TNa, and NKCC2 inhibition substantially reduced thick ascending limb TNa. Both gave rise to diuresis, natriuresis, and kaliuresis, with those effects stronger in female rats. While NCC inhibition was predicted to have only minor impact on renal TNa, it nonetheless had a notable effect of enhancing excretion of Na+, K+, and Cl−, particularly in female rats. Inhibition of ENaC was predicted to have opposite effects on the excretion of Na+ (increased) and K+ (decreased) and to have only a minor impact on whole kidney TNa. Unlike inhibition of other transporters, ENaC inhibition induced stronger natriuresis and diuresis in male rats than female rats. Overall, model predictions agreed well with measured changes in Na+ and K+ excretion in response to diuretics and Na+ transporter mutations.

Estimated Daily Urine Volume and Solute Excretion from Spot Urine Samples to Guide the Therapy of Hyponatremia in SIADH

Background: In hyponatremia, due to the inappropriate secretion of antidiuretic hormone (SIADH), a high versus low solute intake will affect the urine volume (UV) and, hence, the SNa level. The clinical implication of the fractional solute excretion is presented. Methods: In 35 normal controls and 24 patients with SIADH and urine osmolality higher than serum osmolality, we compared exact solute intake obtained from 24 h urine collection, with the estimated value obtained on a urine morning spot sample by the formula: eGFR (L/min) × Sosm × 1440 × FE.Osm (%) = mmol/24 h. The exact UV was compared with the estimated value given by the formula: eGFR × 1440 × S.Creat/U.Creat (for eGFR the MDRD was used). In 65 patients with chronic SIADH, from which a morning spot urine sample was available, we determined the estimated fluid and solute intake. Results: A good correlation was observed between the measured solute output or urine volume and the estimated values obtained from the controls (r = 0.86) as well as in SIADH (r = 0.91). Conclusion: Patients with low solute intake (FE.Osm <1.4%) and low diuresis (V/eCcr <0.8%) should increase their intake by taking oral urea, for example. Patients with high solute intake (FE.Osm >2.5%) and high diuresis (V/eCcr >1.5%) could usually be treated by mild water restriction (< 1.5–21/24 h).

Pathogenetic justification of possibility of antidiuretic hormone use in incontinent women

Hypothesis/aims of study. Urine incontinence seems to include several pathogenetic forms, as efficient therapy is provided by different medications. Commonly used in the treatment of female patients with overactive bladder and nocturnal polyuria is desmopressin which normalizes the water excretion of the kidney, which is disturbed by a presumed inverted rhythm of vasopressin secretion in these patients. The current analysis was undertaken to evaluate the clinical efficiency of desmopressine in incontinent patients with nocturnal polyuria and polyuria. Study design, materials and methods. A total of 84 patients with complaints of urinary incontinence, polyuria (24-urine volume of 40 mL/kg bodyweight or above) or nocturnal polyuria (nocturnal volume/24-h urine volume of 0.33 or above) and 14 control subjects were included. Mean patient age was 43.6 ± 4.6 years, in control subjects 38.5 ± 6.4 (p > 0.05). All participants performed 24h-urinecollection to determine the voided volumes and the levels of creatinine, osmolality, sodium, magnesium and potassium for each sample. A blood sample was taken during the 24-urinecollection to determine the levels of creatinine, osmolality, sodium, magnesium and potassium. The examination of patients with polyuria and nocturnal polyuria was performed twice: in the initial state and one month after the start of treatment with optimal dose of desmopressin. Optimal dose was established through an open-label dose-titration using 0.1 mg, 0.2 mg and 0.4 mg of desmopressin (Minirin). Safety parameters assessed included incidence of adverse events, vital signs and serum sodium levels. Results. In patients with polyuria and nocturnal polyuria the glomerular filtration rate was normal, whereas diuresis and solute (sodium, magnesium, potassium) excretion in night samples in nocturnal polyuria and both in night and day samples in polyuria were increased. The higher diuresis and the higher solute excretion observed in nocturnal polyuria and polyuria are accompanied by an increase of free water reabsorption. In nocturnal polyuria and polyuria a high correlation was found between the free water reabsorption and solute excretion. This occurs against the background of the high night and day osmotic concentration. The statistically significant recovery of renal function occurred in 12 incontinent women with polyuria and 18 with nocturnal polyuria. In these papients there was a statistically significant decrease in diuresis, osmolar clearance and excretion of sodium, potassium and magnesium. Concluding message. As desmopressin affects cells of the thick ascending limb of Henle’s loop, it is likely that nocturnal polyuria and polyuria result from a disturbed regulation of the function of these cells. Normalization can be achieved by desmopressin administration to stimulate V2-receptors, which increase water permeability and water reabsoption in collecting ducts as well as ion reabsorption by cells of the thick ascending limb of Henle’s loop.

Solute transport and oxygen consumption along the nephrons: effects of Na+ transport inhibitors

Sodium and its associated anions are the major determinant of extracellular fluid volume, and the reabsorption of Na+ by the kidney plays a crucial role in long-term blood pressure control. The goal of this study was to investigate the extent to which inhibitors of transepithelial Na+ transport (TNa) along the nephron alter urinary solute excretion and TNa efficiency and how those effects may vary along different nephron segments. To accomplish that goal, we used the multinephron model developed in the companion study (28). That model represents detailed transcellular and paracellular transport processes along the nephrons of a rat kidney. We simulated the inhibition of the Na+/H+ exchanger (NHE3), the bumetanide-sensitive Na+-K+-2Cl− transporter (NKCC2), the Na+-Cl− cotransporter (NCC), and the amiloride-sensitive Na+ channel (ENaC). Under baseline conditions, NHE3, NKCC2, NCC, and ENaC reabsorb 36, 22, 4, and 7%, respectively, of filtered Na+. The model predicted that inhibition of NHE3 substantially reduced proximal tubule TNa and oxygen consumption (QO2). Whole-kidney TNa efficiency, as reflected by the number of moles of Na+ reabsorbed per moles of O2 consumed (denoted by the ratio TNa/QO2), decreased by ∼20% with 80% inhibition of NHE3. NKCC2 inhibition simulations predicted a substantial reduction in thick ascending limb TNa and QO2; however, the effect on whole-kidney TNa/QO2 was minor. Tubular K+ transport was also substantially impaired, resulting in elevated urinary K+ excretion. The most notable effect of NCC inhibition was to increase the excretion of Na+, K+, and Cl−; its impact on whole-kidney TNa and its efficiency was minor. Inhibition of ENaC was predicted to have opposite effects on the excretion of Na+ (increased) and K+ (decreased) and to have only a minor impact on whole-kidney TNa and TNa/QO2. Overall, model predictions agree well with measured changes in Na+ and K+ excretion in response to diuretics and Na+ transporter mutations.

Thienoquinolins exert diuresis by strongly inhibiting UT-A urea transporters

Urea transporters (UT) play an important role in the urine concentration mechanism by mediating intrarenal urea recycling, suggesting that UT inhibitors could have therapeutic use as a novel class of diuretic. Recently, we found a thienoquinolin UT inhibitor, PU-14, that exhibited diuretic activity. The purpose of this study was to identify more potent UT inhibitors that strongly inhibit UT-A isoforms in the inner medullary collecting duct (IMCD). Efficient thienoquinolin UT inhibitors were identified by structure-activity relationship analysis. Urea transport inhibition activity was assayed in perfused rat terminal IMCDs. Diuretic activity of the compound was determined in rats and mice using metabolic cages. The results show that the compound PU-48 exhibited potent UT-A inhibition activity. The inhibition was 69.5% with an IC50 of 0.32 μM. PU-48 significantly inhibited urea transport in perfused rat terminal IMCDs. PU-48 caused significant diuresis in UT-B null mice, which indicates that UT-A is the target of PU-48. The diuresis caused by PU-48 did not change blood Na+, K+, or Cl− levels or nonurea solute excretion in rats and mice. No toxicity was detected in cells or animals treated with PU-48. The results indicate that thienoquinolin UT inhibitors induce a diuresis by inhibiting UT-A in the IMCD. This suggests that they may have the potential to be developed as a novel class of diuretics with fewer side effects than classical diuretics.