Extracellular Volume Contraction Research Articles

Managing new-onset gout in pediatric renal transplant recipients: when, how, to what extent

Hyperuricemia and gout are common among adult renal transplant recipients, but it is rarely reported following pediatric renal transplantations. Treating gout in pediatric kidney transplant recipients presents clinical challenges to the management of both immunosuppressive regimen and hyperuricemia for their effects on serum uric acid levels, renal function and drug interactions. Most renal transplant recipients have a relative impairment of renal clearance of urate due to abnormalities in renal transport, explaining the association of hyperuricemia and decreased glomerular filtration rate. Risk factors for the development of gout include impaired renal function, hypertension, heart failure and diabetes mellitus. Calcineurin inhibitors, particularly cyclosporine, are the most important risk factor for gout in transplant recipients and should not be used in pediatric renal transplant recipients. Diuretic therapy increases the risk of gout by causing extracellular volume contraction with consequent enhancement of proximal tubular reabsorption. Corticosteroids are increasingly replacing nonsteroidal antiinflammatory drugs and colchicine for the treatment of acute gout flares because they have little effect on kidney function. Proper management is aimed at lowering serum uric acid level below 6.0 mg/dL with xanthine oxidase inhibitors such as allopurinol or febuxostat. Allopurinol and mycophenolate mofetil are safer to use in combination than are allopurinol and azathioprine. Febuxostat is an alternative to allopurinol in patients with allopurinol intolerance or hypersensitivity. Pegloticase is indicated for patients with severe gout in whom allopurinol and febuxostat have not been effective or tolerated.

Regulation of renin secretion by renal juxtaglomerular cells

A major rate-limiting step in the renin-angiotensin-aldosterone system is the release of active renin from endocrine cells (juxtaglomerular (JG) cells) in the media layer of the afferent glomerular arterioles. The number and distribution of JG cells vary with age and the physiological level of stimulation; fetal life and chronic stimulation by extracellular volume contraction is associated with recruitment of renin-producing cells. Upon stimulation of renin release, labeled renin granules "disappear;" the number of granules decrease; cell membrane surface area increases in single cells, and release is quantal. Together, this indicates exocytosis as the predominant mode of release. JG cells release few percent of total renin content by physiological stimulation, and recruitment of renin cells is preferred to recruitment of granules during prolonged stimulation. Several endocrine and paracrine agonists, neurotransmitters, and cell swelling converge on the stimulatory cyclic AMP (cAMP) pathway. Renin secretion is attenuated in mice deficient in beta-adrenoceptors, prostaglandin E(2)-EP4 receptors, Gsα protein, and adenylyl cyclases 5 and 6. Phosphodiesterases (PDE) 3 and 4 degrade cAMP in JG cells, and PDE3 is inhibited by cyclic GMP (cGMP) and couples the cGMP pathway to the cAMP pathway. Cyclic AMP enhances K(+)-current in JG cells and is permissive for secretion by stabilizing membrane potential far from threshold that activates L-type voltage-gated calcium channels. Intracellular calcium paradoxically inhibits renin secretion likely through attenuated formation and enhanced degradation of cAMP; by activation of chloride currents and interaction with calcineurin. Connexin 40 is necessary for localization of JG cells in the vascular wall and for pressure- and macula densa-dependent suppression of renin release.

Acute renal failure when exenatide is co-administered with diuretics and angiotensin II blockers

Case (description) the patient is a 20 years old male smoker, who was diagnosed with type 2 diabetes mellitus in 2006. Due to the inadequate response to the previously established treatment, the pharmacotherapy was modified by introducing exenatide (up to 10 μg, twice daily) instead of insulin glargine, but maintaining the treatment with the diuretic and angiotensin II receptor antagonist drugs. Two months later, the patient exhibited a very important intolerance to exenatide (continuous nausea, vomiting, and dehydration), finally leading to ischemic acute renal failure. When the angiotensin II receptor antagonist and exenatide were suspended, a very rapid recovery of renal function was observed. Conclusion ischemic acute renal failure is supposed to be the consequence of the extracellular volume contraction caused by exenatide (the result of continuous nausea and vomiting). This adverse effect could be caused by the co-administration of diuretics and angiotensin II receptor antagonists.

Strong ion difference in urine: new perspectives in acid-base assessment

The plasmatic strong ion difference (SID) is the difference between positively and negatively charged strong ions. At pH 7.4, temperature 37°C and partial carbon dioxide tension 40 mmHg, the ideal value of SID is 42 mEq/l. The buffer base is the sum of negatively charged weak acids ([HCO3-], [A-], [H2PO4-]) and its normal value is 42 mEq/l. According to the law of electroneutrality, the amount of positive and negative charges must be equal, and therefore the SID value is equal to the buffer base value. The easiest assessment of metabolic acidosis/alkalosis relies on the base excess calculation: buffer baseactual - buffer baseideal = SIDactual - SIDideal. The SID approach allows one to appreciate the relationship between acid–base and electrolyte equilibrium from a unique perspective, and here we describe a comprehensive model of this equilibrium. The extracellular volume is characterized by a given SID, which is a function of baseline conditions, endogenous and exogenous input (endogenous production and infusion), and urinary output. Of note, volume modifications vary the concentration of charges in the solution. An expansion of extracellular volume leads to acidosis (SID decreases), whereas a contraction of extracellular volume leads to alkalosis (SID increases). A thorough understanding of acid–base equilibrium mandates recognition of the importance of urinary SID.

Role of sodium and volume in the pathogenesis of hypertension in hemodialysis.

Hypertension is a common finding in chronic hemodialysis (HD) patients. Cardiovascular (CV) disease is the leading cause of death in this population, and hypertension is a significant risk factor for CV events. Understanding the etiology of hypertension in chronic HD patients is critical in order to optimize treatment and reduce the morbidity and mortality associated with hypertension. Although the pathogenesis of hypertension in HD patients is multifactorial, two of the major risk factors are increased extracellular volume and sodium intake. Control of extracellular volume has been shown to normalize blood pressure (BP), but this normalization lags behind the extracellular volume contraction ("lag phenomenon"). A sodium load leads to an increase in BP by causing an increase in extracellular volume, resulting in a transient increase in cardiac output and an increase in total peripheral resistance. Sodium may be implicated in the hypertension of end-stage renal disease (ESRD) patients through hypervolemia-independent mechanisms. Aggressive control of extracellular volume and dietary sodium intake can normalize BP in chronic HD patients and reduce the morbidity associated with hypertension-related CV disease.

Thiazide-induced hypocalciuria is accompanied by a decreased expression of Ca2+ transport proteins in kidney

Thiazide diuretics have the unique characteristic of increasing renal Na+ excretion, while decreasing Ca2+ excretion. However, the molecular mechanism responsible for this thiazide-induced hypocalciuria remains unclear. The present study investigates the effect of thiazides on the expression of the proteins involved in active Ca2+ transport as well as the role of extracellular volume (ECV) status. Hydrochlorothiazide (HCTZ), 12 mg/24 hours, was administered during 7 days to Wistar rats by osmotic minipumps. In addition, ECV contraction was either prevented by Na+ repletion or induced by a low-salt diet. Expression levels of the proteins involved in active Ca2+ transport [i.e., epithelial Ca2+ channel (TRPV5/ECaC1), calbindin-D28K, Na+/Ca2+ exchanger (NCX1)], as well as the thiazide-sensitive Na+ Cl- cotransporter (NCC) were determined by real-time quantitative polymerase chain reaction (PCR) and semiquantitative immunohistochemistry. HCTZ significantly reduced urinary Ca2+ excretion (22%+/- 5% relative to controls). Hematocrit was significantly increased, confirming ECV contraction. In addition, Na+ depletion virtually abolished Ca2+ excretion (8%+/- 1%), while Na+ repletion during HCTZ treatment prevented both ECV contraction and hypocalciuria. HCTZ significantly decreased mRNA expression of TRPV5 (71%+/- 6%), calbindin-D28K (53%+/- 6%), NCX1 (51%+/- 8%) and NCC (50%+/- 11%), regardless of ECV status or calciuresis. Immunohistochemistry revealed reduced TRPV5 (43%+/- 2%), calbindin-D28K (59%+/- 1%) and NCC (56%+/- 4%) abundance. Furthermore, during HCTZ treatment, the subset of tubules coexpressing NCC and calbindin-D28K was significantly reduced (43%+/- 5%) and a disturbed cellular localization of NCC was observed. These data suggest that ECV contraction is a critical determinant of the thiazide-induced hypocalciuria, which is accompanied by a decreased expression of Ca2+ transport proteins.

Randomised controlled trial of postnatal sodium supplementation in infants of 25–30 weeks gestational age: effects on cardiopulmonary adaptation

BACKGROUNDIt has previously been shown that, in preterm babies, routine sodium supplementation from 24 hours after birth is associated with increased risk of oxygen dependency and persistent expansion of the...

Role of adenosine in tubuloglomerular feedback and acute renal failure.

1. Adenosine (ADO) can induce renal vasoconstriction and a fall in glomerular filtration rate. When the rate of ATP hydrolysis prevails over the rate of ATP synthesis the kidney generates ADO at an enhanced rate. 2. Tubuloglomerular feedback (TGF) is the vascular response to changes of the NaCl concentration in the tubular fluid at the macula densa segment, which is the result of transepithelial electrolyte reabsorption by the proximal tubule and the loop of Henle. 3. TGF can be inhibited by ADO-A1 receptor antagonists and is potentiated by substances that can elevate extracellular ADO concentrations. These observations led to the hypothesis that ADO is an element of the signal transmission processes in the juxtaglomerular apparatus. 4. Renal ischaemia and nephrotoxic substances can induce acute renal failure (ARF). ADO receptor antagonists have been shown to ameliorate renal function in several different models of ARF in laboratory animals and humans. 5. A number of factors, such as extracellular volume contraction, low NaCl diet, angiotensin II and cyclooxygenase inhibitors enhance to a similar extent: (a) the renal vascular response to endogenous and exogenous ADO; (b) the TGF response of the nephron; and (c) the severity of ARF. All three phenomena are susceptible to antagonism by ADO receptor antagonists. 6. Therefore, we conclude that ADO plays a significant role in normal and pathological states of kidney function.

Renal Bicarbonate Excretion in Extremely Low Birth Weight Infants

To test the hypothesis that due to the immaturity of their kidneys extremely low birth weight infants lose large amounts of bicarbonate in their urine. Urine and blood samples collected every 8 to 12 hours for the first 4 days of life from 22 preterm infants 23 to 29 weeks' gestation weighing 540 to 982 g at birth were prospectively studied. As described previously, three phases of fluid homeostasis were identified. The first phase (prediuresis) was a period of low urine output followed by a period of spontaneous diuresis/natriuresis (diuretic phase) and then by a phase when urine output varied according to fluid intake (postdiuresis). Sodium, potassium, chloride, and bicarbonate excretion rates and bicarbonate balance (bicarbonate or acetate infused minus bicarbonate excreted) were calculated for each of the three phases. Urinary excretion of sodium, potassium, chloride, and bicarbonate increased from the prediuretic to the diuretic phase and decreased from the diuretic to the postdiuretic phase. During the diuretic phase 88% of renal sodium excretion was accompanied by excretion of chloride. Bicarbonate balance was positive in all three fluid phases. Cumulative renal bicarbonate loss over the first 4 days of life was 1.9 +/- 0.5 meq/kg (SD) and the cumulative bicarbonate balance was +4.4 +/- 4.1 meq/kg (SD). The glomerular filtration rate, filtered load of bicarbonate, and absolute tubular reabsorption of bicarbonate significantly increased from the prediuretic to the diuretic phase, while fractional reabsorption of sodium and chloride decreased between these two phases. The fractional reabsorption of bicarbonate did not change from prediuresis to diuresis, but increased from diuresis to postdiuresis and consequently from prediuresis to postdiuresis. Contrary to our original hypothesis, the total renal bicarbonate excretion of extremely low birth weight infants in the first 4 days of life is low and the net bicarbonate balance is positive. The anion predominantly accompanying the excretion of sodium in all three phases is chloride and not bicarbonate. Bicarbonate excretion appears to be independent of sodium excretion during these phases. The increase in renal tubular bicarbonate reabsorption during the first week of life may be associated with extracellular volume contraction.

Syndrome of flank pain and acute renal failure after binge drinking and nonsteroidal anti-inflammatory drug ingestion.

The binge drinking of alcohol combined with the ingestion of a nonsteroidal anti-inflammatory drug (NSAID) is a recently described cause of reversible acute renal failure. The pathogenetic mechanisms leading to acute tubular necrosis in this setting include the initial compromise in renal perfusion due to alcohol-induced extracellular volume contraction and the superimposed renal hemodynamic alterations induced by the NSAID that interfere with the renal autoregulation. Although alcohol may also cause rhabdomyolysis leading to acute tubular necrosis, this is usually not apparent in these cases. Previously, only three such cases have been reported but the incidence is likely to be higher in view of the prevalence of alcohol and NSAID use. Herein is presented another patient in whom the features of flank pain and acute renal failure in association with binge drinking and NSAID ingestion constitute a characteristic syndrome.

Posttransplant erythrocytosis

A case of posttransplant erythrocytosis in a 51-year-old diabetic man is described. This problem, which can occur in 5 to 15% of renal transplant patients, can result from a contracted plasma volume (diuretics, pressure natriuresis, or glycosuria) or from a true elevation in red blood cell mass. Once the diagnosis of true erythrocytosis is made by a radiolabeled red blood cell mass study, secondary causes such as hypoxia, liver disease, polycythemia rubra vera, renal artery stenosis, and cystic kidney disease should be excluded. Posttransplant erythrocytosis has only been observed in renal transplant recipients and appears to be more frequent with cyclosporine compared with azathioprine therapy. An inappropriately high level of erythropoietin has been described in some, but not all patients, suggesting stimulation of erythropoietin production as the mechanism. Posttransplant erythrocytosis can be associated with an increased incidence of thrombotic events. The presence of this potential complication has prompted intervention to maintain the hematocrit below 50 to 55%. Measures such as discontinuation of diuretics as well as better control of blood pressure and plasma glucose should be used to facilitate the correction of extracellular volume contraction. Phlebotomy has been the most accepted intervention to intermittently lower the hematocrit when needed, but this can lead to iron deficiency. Newer therapeutic modalities are now being used to treat the problem medically. Theophylline, which reduces adenosine-mediated erythropoietin synthesis, is effective but may be associated with side effects.(ABSTRACT TRUNCATED AT 250 WORDS)

3 - Endocrine control of electrolyte balance during development

The endocrine control of electrolyte balance during development is reviewed. It is suggested that the high urinary sodium excretion observed in premature infants may be secondary to the immaturity of the adrenal gland to adequately increase the secretion of aldosterone (Sulyok et al, 1979b), and to the inability of the distal tubule to respond appropriately to a rise in circulating aldosterone levels (Sulyok et al, 1979a). On the other hand, the elevated plasma aldosterone levels observed in term newborn infants may play an important role in the blunted response of the newborn kidney to saline loading (Sulyok et al, 1979a; Spitzer, 1982). The ability of ANP to induce a natriuresis and to contribute to fluid and electrolyte homeostasis during development has been investigated. It has been found that the immature kidney is less responsive to ANP than later in life (Chevalier et al, 1988; Robillard et al, 1988). On the other hand, it has been suggested that a rise in plasma ANP during the first five days of life may contribute to the physiological weight loss associated with the extracellular volume contraction occurring shortly after birth (Tulassay et al, 1987). The role of glucocorticoids, prostaglandins and the kallikrein-kinin system in regulating electrolyte balance during development is also reviewed.

Developmental Outcome of Infants Exposed to a Chloride-Deficient Diet

In 1980, a small group of infants were identified whose initial signs and symptoms included failure to thrive, lethargy, anorexia, and weakness. Initial electrolyte determinations indicated a severe metabolic alkalosis with hypochloremia and hypokalemia. In subsequent investigations by the Centers for Disease Control, a large number of infants with the same signs and symptoms and biochemical abnormalities were identified. All of these infants were found to be ingesting formulas markedly chloride deficient. In studies of this group of infants with dietary chloride deficiency, high levels of renin and aldosterone were found. The postulated mechanism for the underlying electrolyte abnormalities was the deficiency of chloride in the diet that caused extra-cellular volume contraction, stimulating the release of renin and aldosterone.

Assessment of the pathogenetic role of physical exercise in renal stone formation.

The effects of moderate physical exercise (performed on a bicycle ergometer to 70-75% of maximum oxygen consumption) without fluid replenishment on urinary chemistries and crystallization of kidney stone-forming substances were compared to those of rest in six normal subjects. Moderate physical exercise significantly decreased urinary pH [from 6.35 +/- 0.32 (+/-SD) to 5.79 +/- 0.33; P less than 0.05] and citrate [from 121.1 +/- 63.5 to 88.2 +/- 44.4 mg/6-h period from initiation of physical exercise; P less than 0.05 (630 +/- 331 to 459 +/- 231 mumol/6 h)], owing to induced metabolic acidosis. The total renal excretion of stone-forming constituents decreased [for example, calcium from 31.2 +/- 15.8 to 21.4 +/- 6.5 mg/6 h (0.8 +/- 0.4 to 0.5 +/- 0.2 mmol/6 h), phosphorus from 155 +/- 42 to 127 +/- 27 mg/6 h (5.01 +/- 1.4 to 4.1 +/- 0.9 mmol/6 h), and uric acid from 172 +/- 60 to 117 +/- 13 mg/6 h (1.0 +/- 0.4 to 0.7 +/- 0.1 mmol/6 h), each P less than 0.05], probably due to extracellular volume contraction (from sweating) and enhanced renal tubular reabsorption. However, the urinary concentration of stone-forming constituents significantly increased during and after moderate exercise because of the fall in urinary volume from 847 +/- 312 to 290 +/- 36 ml/6 h (P less than 0.01). Thus, urinary calcium oxalate saturation increased significantly from 2.62- to 6.68-fold saturation (P less than 0.01). The urinary undissociated uric acid concentration significantly rose [from 31.6 +/- 24.8 to 125.7 +/- 60.3 mg/L (0.19 +/- 0.15 to 0.76 +/- 0.36 mmol/L; P less than 0.01)], due to higher total uric acid concentration and reduced urinary pH. The saturation of calcium phosphate (brushite) did not change significantly, because the rise in urinary calcium concentration was compensated for by reduced phosphate dissociation (from lower urinary pH). The propensity for spontaneous precipitation of calcium oxalate was greater after exercise, as less soluble oxalate was required to elicit nucleation of calcium oxalate [58.0 +/- 21.2 to 49.0 +/- 16.4 mg/L (644 +/- 236 to 544 +/- 182 mumol/L); P less than 0.05]. The results suggest that moderate physical exercise, without increased fluid intake to compensate for excessive sweating, may cause the crystallization of uric acid and calcium oxalate in urine and may enhance the risk of the formation of renal stones composed of these salts.

Acidification is inhibited in late proximal convoluted tubule during chronic metabolic alkalosis.

In vivo microperfusion was used to assess the changes in the active and passive components of bicarbonate absorption in the rat late proximal tubule during chronic metabolic alkalosis. In tubules perfused with 40 mM bicarbonate, net bicarbonate absorption was inhibited and normal flow dependence was attenuated during alkalosis, compared with values in normal tubules perfused with 40 or even 25 mM bicarbonate concentrations. Under all conditions, bicarbonate back leak was small and contributed little to alterations in net bicarbonate transport, even though bicarbonate permeability was reduced by approximately 75% during chronic metabolic alkalosis and was flow dependent. Suppression of net bicarbonate absorption during chronic metabolic alkalosis was instead attributable to inhibition of proton secretion as a function of both luminal bicarbonate concentration and flow rate. At the highest level of bicarbonate delivery to yield maximal acidification rates, proton secretion during alkalosis was diminished by 38% (from 216 +/- 15 to 133 +/- 10 peq X mm-1 X min-1, P less than 0.001). In conclusion, despite extracellular volume contraction, potassium deficiency, and reduction in bicarbonate permeability during chronic metabolic alkalosis, net bicarbonate absorption in the late proximal convoluted tubule is depressed as a function of luminal bicarbonate concentration and flow rate because acidification is inhibited by hyperbicarbonatemia/alkalemia.

Atrial natriuretic peptide and extracellular volume contraction after birth.

Plasma concentrations of atrial natriuretic peptide (ANP) were measured in full-term newborns immediately after birth and on the 3rd, 5th, 7th and 10th day of life. The ANP concentrations were within the normal range in the first hours of life. Plasma concentrations of ANP had increased significantly on the 3rd and 5th day of life, while body weight decreased continuously. After the 5th day of life ANP concentration decreased continuously reaching its minimum on the 10th day whereas body weight increased. The mechanism behind ANP release shortly after birth is not known. The increase in ANP concentration in plasma may however induce changes in body fluid compartments shortly after birth which would result in physiological weight loss.

Renal Function in Cystic Fibrosis

The effect of saline extracellular volume expansion (4 ml/min/10 kg b.w. X 60 min) on renal function has been studied in patients with cystic fibrosis (CF) and in normal age-matched controls. Basal values for glomerular filtration rate (GFR), renal plasma flow (RPF), tubular sodium and chloride (Na, Cl) handling were similar in both groups. Saline expansion resulted in an increase in GFR and RPF in the CF patients: 127 +/- 18 ml/min/1.73 sqm BSA to 166 +/- 5; p less than 0.001, but not in the control group: 112 +/- 10 to 120 +/- 20. These hemodynamic changes were associated with increased proximal tubular reabsorption of NaCl in the CF patients whereas controls had reduced NaCl reabsorption. Renin and aldosterone levels suggested that increased NaCl reabsorption in CF patients was not secondary to chronic extracellular volume contraction or salt loss. These results support the hypothesis that the renal tubule is involved in the generalised electrolyte transport disorder exhibited in other epithelial structures. This study also indicated that the regulation of renal hemodynamics is altered in CF. The relationship between the disorder of proximal tubular salt handling and changes in renal hemodynamics is not known, but the observed changes imply a tubulo-glomerular feedback mechanism.

The adolescent with essential hypertension.

Clinical features in a comparably studied group of hypertensive and normotensive adolescents are described. Hypertensive hyperreninemia occurred in four of 28 hypertensive adolescents; suppressed plasma renin activity was found in five of 27 hypertensive adolescents. Only one of five adolescents identified as having suppressed plasma renin activity after ingesting a low-salt diet for three days had a hyporesponsive response to acute extracellular volume contraction. Pressure natriuresis was documented in six of 32 adolescents. Compared to normotensive, the hypertensive group was found to have elevated levels of serum uric acid. Plasma renin activity was higher in hypertensive children with hyperuricemia than in those with normouricemia. The hypertensive adolescents also had higher levels of serum calcium and phosphorus. Two-thirds of the hypertensive adolescents had echocardiographic changes of myocardial hypertrophy. No ophthalmologic nor renal abnormalities were documented in the hypertensive group. A review of factors influencing blood pressure changes during childhood and current considerations for therapy are included.

Bartter's Syndrome

We were able to separate Bartter's syndrome patients into two groups: Group 1 patients are seen at a young age, with hyponatremia and episodes of extracellular volume contraction. Group 2 patients are older and most have tetany; plasma sodium values and renal sodium balances are normal. Plasma potassium values are lower and plasma renin activity and plasma magnesium levels are higher in group 1 than in group 2. It may be that all patients with Bartter's syndrome manifest the features of both groups, group 1 patients with time developing into group 2 patients. These observations have important implications in the treatment of patients with Bartter's syndrome.

Transfer of cefazolin into human milk

phate load will be rapidly excreted by the kidney in the presence of normal glomerular and tubular function, but only in conjunction with a cation to preserve electroneutrality. This is a possible explanation for the large concentration of cations (sodium and potassium) noted in the random urine specimen obtained at the time of the initial admission. In the presence of extracellular volume contraction and increased aldosterone production, a significant proportion of this cation loss could be potassium. The use of enemas, especially hypertonic phosphate enemas, has become routine in pediatrics in preparation for roentgen studies and in the treatment of chronic constipation. Although enemas given to normal individuals usually do not cause electrolyte imbalance, children with abnormal colons or impaired renal function are especially prone to fluid and electrolyte disturbances following the administration of enemas. If the chronic use of enemas cannot be avoided, such patients should be monitored with periodic determinations of serum electrolyte, phosphorus, and calcium concentrations.