Reduced Urine Output Research Articles

Identification of novel selective V 2 receptor non-peptide agonists

Peptides with agonist activity at the vasopressin V 2 receptor are used clinically to treat fluid homeostasis disorders such as polyuria and central diabetes insipidus. Of these peptides, the most commonly used is desmopressin, which displays poor bioavailability as well as potent activity at the V 1b receptor, with possible stress-related adverse effects. Thus, there is a strong need for the development of small molecule chemistries with selective V 2 receptor agonist activity. Using the functional cell-based assay Receptor Selection and Amplification Technology (R-SAT ®), a screening effort identified three small molecule chemotypes (AC-94544, AC-88324, and AC-110484) with selective agonist activity at the V 2 receptor. One of these compounds, AC-94544, displayed over 180-fold selectivity at the V 2 receptor compared to related vasopressin and oxytocin receptors and no activity at 28 other G protein-coupled receptors (GPCRs). All three compounds also showed partial agonist activity at the V 2 receptor in a cAMP accumulation assay. In addition, in a rat model of central diabetes insipidus, AC-94544 was able to significantly reduce urine output in a dose-dependent manner. Thus, AC-94544, AC-88324, and AC-110484 represent novel opportunities for the treatment of disorders associated with V 2 receptor agonist deficiency.

Novel Treatment for Lithium-Induced Nephrogenic Diabetes Insipidus Rat Model Using the Sendai-Virus Vector Carrying Aquaporin 2 Gene

Congenital nephrogenic diabetes insipidus (NDI) is a chronic disorder involving polyuria and polydipsia that results from unresponsiveness of the renal collecting ducts to the antidiuretic hormone vasopressin. Either of the genetic defects in vasopressin V2 receptor or the water channel aquaporin 2 (AQP2) cause the disease, which interfere the water reabsorption at the epithelium of the collecting duct. An unconscious state including a perioperative situation can be life threatening because of the difficulty to regulate their water balance. The Sendai virus (SeV) vector system deleting fusion protein (F) gene (SeV/DeltaF) is considered most suitable because of the short replication cycle and nontransmissible character. An animal model for NDI with reduced AQP2 by lithium chloride was used to develop the therapy. When the SeV/DeltaF vector carrying a human AQP2 gene (AQP2-SeV/DeltaF) was administered retrogradely via ureter to renal pelvis, AQP2 was expressed in the renal collecting duct to reduce urine output and water intake by up to 40%. In combination with the retorograde administration to pelvis, this system could be the cornerstone for the applicable therapies on not only NDI patients but also other diseases associate with the medullary collecting duct.

Renal Transplant Compartment Syndrome: A Case Report

An unusual case of early double kidney transplant dysfunction due to abdominal compartment syndrome is herein reported. A 62-year-old woman on peritoneal dialysis underwent dual kidney transplantation. The grafts were positioned extraperitoneally in both iliac possae using standard techniques. Surgical procedures and immediate postoperative period were uneventful. The urine output was immediate and the creatinine decreased, but in a few days she developed severe ascites with reduced urine output, increased creatinine, and progressive changes on Doppler ultrasound. The patient underwent paracentesis: the kidney function recovered as well as the Doppler ultrasound. Kidney biopsy was negative for rejection or renal pathology. Graft dysfunction was related to the presence of ascites. A catheter inserted in the abdomen measured intra-abdominal pressure (IAP) of 14 mm Hg. IAP correlated with renal function showing that IAP probably explained renal flow modifications.

Tonicity‐responsive activation of NFATc by calcineurin Aβ in the inner medullae

Previously, we found that nuclear factor of activated T cell (NFATc) is regulated by the β isoform of calcineurin (CaN). In vivo, NFATc‐driven luciferase expression is highest in the renal inner medullae (IM) and loss of the β isoform significantly decreases NFATc‐transcriptional activity. Expression and activity of NFATc in the IM suggests a role for CaNβ/NFATc in response to tonicity. To explore this, activation of CaN in response to calcium ionophore, glucose, mannitol, urea, and NaCl was examined. CaN activity in wildtype renal fibroblasts was increased by changes in tonicity in a dose‐dependent manner. CaN activity in β−/− cells, in contrast, was no longer regulated by tonicity. To examine the tonicity response in vivo, wildtype and β−/− mice were thirsted for 32 hours. Urine output and osmolarity were measured and kidneys were harvested for analyses. Wildtype mice had decreased urine output and increased urine concentration, as expected. This was accompanied by an increase in NFATc‐luciferase activity in the IM. β−/− mice, however, did not reduce urine output and did not concentrate their urine despite the period of thirsting. In addition, despite normal basal urine concentration, β−/− mice failed to increase urine osmolality in response to the vasopressin analog DDAVP. In conclusion, CaNβ is activated in vitro in response to hypertonicity and loss of β in vivo impairs urine concentration.

Urine Neutrophil Gelatinase-Associated Lipocalin and Interleukin-18 Predict Acute Kidney Injury after Cardiac Surgery

Background. About 30–50% patients develop acute kidney injury (AKI) after cardiac surgery, which is still diagnosed by serum creatinine on clinic. However, the increase of serum creatinine is insensitive and delayed. The aim of this study is to test the hypothesis that neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 (IL-18) are early biomarkers for AKI in patients after cardiac surgery. Methods. Thirty-three cases undergoing cardiac surgery were classified into an AKI group and non-AKI group, according to the AKI definition (> 26.5 μmol/L increase of serum creatinine, more than or equal to 50% increase of serum creatinine within 48 h, or a reduction in urine output < 0.5 mL/Kg per hour for more than six hours). The concentrations of serum NGAL, urine NGAL, and urine IL-18 at different time-points were measured. Results. Nine cases (27.27%) developed postoperative AKI, but diagnosis with serum creatinine was 12–48 h postoperation. The concentrations of serum NGAL were not significantly increased postoperation. The concentrations of urine NGAL and IL-18 were significantly increased in the AKI group, which reached the peak at 2–4 h postoperation, and a more significant difference could be seen after correction for urine creatinine. The concentrations of urine NGAL and IL-18 2 h postoperation, either corrected for urine creatinine or not, showed good sensitivity and specificity. Increased levels of urine NGAL and IL-18 2 h postoperation were significantly correlated with increased level of serum creatinine 12 h postoperation. Logistic regression analysis showed that urine NGAL corrected for urine creatinine 2 h postoperation and urine IL-18 2 h postoperation emerged as powerful independent predictors of AKI after cardiac surgery. Conclusions. The concentrations of urine NGAL and IL-18 could be useful biomarkers for AKI in patients after cardiac surgery, especially after correction for urine creatinine.

Acute kidney injury: time to shift from creatinine to the estimated glomerular filtration rate?

Acute kidney injury (AKI) is a complex disorder for which currently there is no accepted definition. Although several groups are working on developing and validating biomarkers of kidney injury and the glomerular filtration rate (GFR), the proposed diagnostic criteria from the Acute Kidney Injury Network are based on an absolute increase in serum creatinine ≥0.3 mg/dl (≥26.4 μmol/l), a percentage increase in serum creatinine ≥50% (1.5-fold from baseline), or a reduction in urine output (documented oliguria <0.5 ml/kg per hour for more than 6 hours) [1]. A recent report from the Laboratory Working Group of the National Kidney Disease Education Program, however, recommends that serum creatinine alone should not be used to assess the GFR or to detect the presence of kidney disease because it is affected by the GFR and by factors independent of the GFR, including age, sex, race, body size, diet, certain drugs, and laboratory analytical methods [2]. Rather, the Working Group suggests implementing the estimated GFR using the Modification of Diet in Renal Disease (MDRD) study [2]. In analogy with chronic kidney disease, implementation of the MDRD equation would probably grant more clinically useful information to assess AKI.

Improving Outcomes from Acute Kidney Injury

Acute kidney injury is a common clinical problem that is defined by an abrupt increase in serum creatinine over 48 h resulting from injury or insult that causes a functional or structural change in the kidney. Recent epidemiologic studies demonstrate wide variation in causes and risk factors

Improving rehydration in thermally dehydrated rats with sucrose solution

After heat exposure, rats do not consume enough water to rehydrate completely. We investigated the potential of providing access to both water and sucrose solution to improve rehydration in rats. A secondary goal was to determine if thermal dehydration alters the preference rats exhibit for sucrose solution. During the experiments, male Sprague-Dawley rats had access to either water, 10% sucrose solution, or both water and 10% sucrose solution. Experiments were carried out on rats at 25°C for four hours with access to fluids and rats exposed to 37.5°C for four hours without access to fluids (thermal dehydration) and then allowed access to fluids for 4 hours at 25°C. At 25°C, rats allowed access to sucrose solution alone or with water drank over 10 times as much fluid as rats allowed access to water alone and produced 4 times more urine. Rats allowed access to fluid following heat exposure had increased water intake but not sucrose solution intake and had reduced urine output compared to the rats at 25°C. Thermally dehydrated rats allowed access to sucrose solution alone or water and sucrose solution had significantly higher levels of rehydration than rats allowed access to water alone. Thermal dehydration greatly reduced the preference for sucrose solution. Although rehydration is improved by providing rats with access to sucrose solution, this benefit may be offset by hyponatremia. Supported by NSF-REU grant DBI-0139035.

COX-2 activity transiently contributes to increased water and NaCl excretion in the polyuric phase after release of ureteral obstruction

Release of bilateral ureteral obstruction (BUO) is associated with reduced expression of renal aquaporins (AQPs), polyuria, and impairment of urine-concentrating capacity. Recently, we demonstrated that 24 h of BUO is associated with increased cyclooxygenase (COX)-2 expression in the inner medulla (IM) and that selective COX-2 inhibition prevents downregulation of AQP2. In the present study, we tested the hypothesis that COX-2 activity increases in the postobstructive phase and that this increase in COX-2 activity contributes to polyuria and impaired urine-concentrating capacity. We examined the effect of the selective COX-2 inhibitor parecoxib (5 mg.kg(-1).day(-1) via osmotic minipumps) on renal functions and protein abundance of AQP2, AQP3, Na-K-2Cl cotransporter type 2 (NKCC2), and Na-K-ATPase 3 days after release of BUO. At 3 days after release of BUO, rats exhibited polyuria, dehydration and urine and IM tissue osmolality were decreased. There were inverse changes of COX-1 and COX-2 in the IM: COX-2 mRNA, protein, and activity increased, while COX-1 mRNA and protein decreased. Parecoxib reduced urine output 1 day after release of BUO, but sodium excretion and glomerular filtration rate were unchanged. Parecoxib normalized urinary PGE(2) and PGI(2) excretion and attenuated downregulation of AQP2 and AQP3, while phosphorylated AQP2 and NKCC2 remained suppressed. Parecoxib did not improve urine-concentrating capacity in response to 24 h of water deprivation. We conclude that decreased NKCC2 and collapse of the IM osmotic gradient, together with suppressed phosphorylated AQP2, are likely causes for the impaired urine-concentrating capacity and that COX-2 activity is not likely to mediate these changes in the chronic postobstructive phase after ureteral obstruction.

Acute Mountain Sickness: Influence of Fluid Intake

High altitude and exposure to cold are associated with significant levels of dehydration because of cold-altitude urine output, high energy expenditures, and poor access to water. The aims of the present study were to measure the fluid intake and urine output among military mountaineers during their stay at high altitude and to study the level of fluid intake and decrease in urine output in relation with acute mountain sickness (AMS). This study used an analytic prospective follow-up design of hydration-dehydration conditions of a group of mountaineers with similar characteristics (military group). Data collected each day included quantity and type of fluid intake, urine output in 24 hours, other fluid output (as diarrhea or vomiting), and symptoms or signs of AMS according to the Lake Louise consensus score. Values are given as mean +/- SE. A 1-factor analysis of variance procedure and t test were used to compare variables. The mountaineers consumed a variety of fluids, including water, tea, coffee, soup, Isostar, and milk. Daily fluid intake was 2800 +/- 979 mL, with a maximum intake of 4700 mL. Daily urine output was 1557 +/- 758 mL. When we stratify our sample at the median by fluid intake, a significant correlation is detected with mean balance and mean urine output. Mountaineers developing AMS demonstrated reduced urine output (mean 1336 mL) when compared with those without AMS (mean 1655 mL). We found that fluid intake was associated but insignificantly correlated with incidence and degree of AMS. Past research suggests that vigorous hydration decreases incidence and severity of AMS and other altitude illnesses. Our results also imply that aggressive fluid intake is protective, but our limited sample size yielded insufficient power to demonstrate a statistically significant difference.

Cochrane review: Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants

AbstractBackgroundA patent ductus arteriosus (PDA) often complicates the clinical course of preterm infants and increases the risk of intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), chronic lung disease (CLD) and death. The standard treatment to close a PDA is indomethacin. Its use is associated with renal, gastrointestinal and cerebral side‐effects. Ibuprofen has been shown to be effective in closing a PDA without reducing blood flow velocity to the brain, gut or kidneys.ObjectivesTo determine the effectiveness and safety of prophylactic ibuprofen compared to placebo/no intervention or other cyclo‐oxygenase inhibitor drugs (indomethacin, mefenamic acid, etc) in the prevention of PDA in preterm infants.Search strategyRandomized controlled trials comparing prophylactic ibuprofen use with placebo/no intervention/indomethacin were identified by searching the Cochrane Central Register of Controlled Trial (CENTRAL, The Cochrane Library, Issue 3, 2005), MEDLINE (1966‐July 2005), CINAHL (1982‐July 2005), EMBASE (1980‐July 2005), reference lists of published trials and abstracts published in Pediatric Research (1990‐July 2005). No language restrictions were applied.Selection criteriaRandomized or quasi‐randomized controlled trials comparing use of ibuprofen with placebo/no intervention or other cyclo‐oxygenase inhibitor drugs (indomethacin, mefenamic acid, etc) for the prevention of PDA in preterm and/or low birth weight infants.Data collection and analysisData regarding the clinical outcomes including presence of PDA on day three and day seven, need for surgical ligation, need for rescue treatment with cyclo‐oxygenase inhibitors, IVH, mortality, renal and gastrointestinal complications were extracted. Meta‐analyses were performed using RevMan 4.2 and treatment estimates were reported as weighted mean difference (WMD), typical relative risk (RR), typical risk difference (RD) and, if statistically significant, number needed to treat (NNT) or number needed to harm (NNH), along with their 95% confidence intervals (CI).Main resultsFour trials (n = 672) were included in the review. There was a statistically significant decrease in the incidence of PDA on day three in the ibuprofen group [typical RR 0.37 (95% CI 0.29, 0.49); typical RD ‐0.29 (95% CI ‐0.35, ‐0.22); NNT 3 (95% CI 3, 5); 4 trials, n = 672], in the need for rescue treatment with cyclo‐oxygenase inhibitors [typical RR 0.17 (95% CI 0.11, 0.27), typical RD ‐0.27 (95% CI ‐0.35, ‐0.22); NNT 4 (95%CI 3, 5), and in the need for surgical ligation [typical RR 0.34 (95% CI 0.14, 0.81), typical RD ‐0.04 (95% CI ‐0.07, ‐0.01); NNT 25 (95% CI 14, 100). The PDA had closed spontaneously by day three in 60% of the neonates in the control group. There was a significant increase in the serum creatinine levels in the ibuprofen group [WMD 0.13 mg/dl (95% CI 0.08, 0.17); 2 trials, n = 495]. Ibuprofen reduces urine output. There were no statistically significant differences in mortality, grade 3/4 intraventricular hemorrhage, chronic lung disease at 28 days or 36 weeks, necrotizing enterocolitis, gastrointestinal hemorrhage, intestinal perforation or time to reach full feeds. One trial (Gournay 2002) (n = 135) reported on three infants in the ibuprofen group who developed pulmonary hypertension responsive to nitric oxide treatment.Authors' conclusionsProphylactic use of ibuprofen reduces the incidence of PDA, the need for rescue treatment with cyclo‐oxygenase inhibitors and surgical closure. However, in the control group, the PDA had closed spontaneously by day three in 60% of the neonates. Prophylactic treatment therefore exposes a large proportion of infants unnecessarily to a drug that has important side effects (mainly involving the kidneys) without conferring any important short term benefits. Prophylactic treatment with ibuprofen is not recommended. Until long‐term follow‐up results are published from the trials included in this review, no further trials of prophylactic ibuprofen are recommended.Plain language summaryIbuprofen may prevent PDA, a common complication for preterm or very small babies, but more research is needed into possible serious adverse effectsA common complication for very preterm (premature) or very small babies is patent ductus arteriosus (PDA). PDA is an open vessel that channels blood from the lungs to the body. It should close after birth, but sometimes remains open because of the baby's premature stage of development. PDA can lead to life‐threatening complications. Indomethacin is successful in causing PDA closure, but can cause serious adverse effects. Another option is the drug ibuprofen, which can be given to try and prevent PDA. The review of trials found that ibuprofen can prevent PDA, but more research is needed on possible serious adverse effects.

A Novel Phospholipid Derivative of Indomethacin, DP-155 [Mixture of 1-Steroyl and 1-Palmitoyl-2-{6-[1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetamido]hexanoyl}-sn-glycero-3-phosophatidyl Choline], Shows Superior Safety and Similar Efficacy in Reducing Brain Amyloid β in an Alzheimer's Disease Model

Indomethacin has been suggested for the treatment of Alzheimer's disease (AD), but its use is limited by gastrointestinal and renal toxicity. To overcome this limitation, D-Pharm Ltd. (Rehovot, Israel) developed DP-155 (mixture of 1-steroyl and 1-palmitoyl-2-{6-[1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetamido] hexanoyl}-Sn-glycero-3-phosophatidyl [corrected] choline), a lecithin derivative of indomethacin. Safety was tested by daily oral administration of DP-155 or indomethacin to rats in a dose range of 0.007 to 0.28 mmol/kg. The prevalence of gastrointestinal ulceration was significantly lower (10-fold) for DP-155 than for indomethacin, and the ulcerations were delayed. Signs of renal toxicity, namely reduced urine output and increased urine N-acetyl glycosaminidase to creatinine ratio, were 5-fold lower for DP-155. Indomethacin, but not an equimolar dose of DP-155, reduced urine bicyclo-prostaglandin E(2). An equimolar oral dose of DP-155 or indomethacin, administered every 4 h for 3 days, was equally efficacious in reducing the levels of Abeta42 in the brains of Tg2576 mice. Indomethacin was the principal metabolite of DP-155 in the serum. After DP-155 oral administration, indomethacin's half-life in the serum and the brain was 22 and 93 h, respectively, compared with 10 and 24 h following indomethacin oral administration. The brain to serum ratio was 3.5 times higher for DP-155 than indomethacin. This finding explains the efficacy of DP-155 in reducing Abeta42 brain levels, despite the low systemic blood concentrations of indomethacin derived from DP-155. In conclusion, compared with indomethacin, DP-155 has significantly lower toxicity in the gut and kidney while maintaining similar efficacy to indomethacin in lowering Abeta42 in the brains of Tg2576 mice. This superior safety profile highlights DP-155's potential as an improved indomethacin-based therapy for AD.

Bladder perforation and development of a vesico - vaginal fistula following laparoscopic assisted vaginal hysterectomy: case report

Bladder injury with subsequent development of a Vesico-Vaginal Fistula following a Laparoscopic Assisted Vaginal Hysterectomy is reported. The injury was not recognised intra--operatively or in the immediate post-operative period. On the third post-operative day, the patient complained of abdominal distention, and a reduced urine output was noted. There was no haematuria. Conservative management by continuous bladder drainage was not successful. A low-pressure cystogram done on day eight revealed a bladder leakage. On day 21, a repeat low-pressure cystogram showed a vesico-vaginal fistula. A successful transvesical repair by laparotomy was undertaken on day 23. The possible mechanisms of injury, prevention and the principles of management are discussed.

Massive postoperative polyuria following total gastrectomy for gastric cancer

Massive postoperative polyuria is rare, except in neurosurgery patients. Here we report excessive polyuria in a 59-year-old woman following total gastrectomy for advanced gastric cancer. The etiology of the patient's polyuria was unknown. Urine output was measured hourly and replaced with Ringer's lactate solution at 80% of measured volume. The rate of urine output during 9 postoperative days ranged from 900 to 2700 ml.h(-1). Several administrations of an antidiuretic hormone (ADH) analogue were ineffective in reducing urine output, suggesting a possible relationship of the massive polyuria to nephrogenic diabetes insipidus. Following oral administration of a thiazide diuretic, known to exert an antidiuretic action in nephrogenic diabetes insipidus, urine output was dramatically reduced. We conclude that this case of massive polyuria probably resulted from postoperative nephrogenic diabetes insipidus.

Changes of Serum ADH Level during Matoidectomy under General Anesthesia

Background: Markedly reduced urine have been commonly observed during mastoidectomy under general anesthesia. The aim of study was to evaluate the surgery-related mechanism of reduced urine during mastoidectomy. Methods: 11 patients undergoing mastoidectomy were studied. Blood samples were drawn from CVP line inserted through right internal jugular vein just before drilling (Pre-D); at 15 min after drilling (D-15); at the time closest to the inner ear (CHP-1); at 15 min (CHP-2) and 30 min (CHP-3) after CHP-1 and just before emergence (End). MAP, HR, temperature, CVP, and urine output (UO) were recorded at each period. 0.9% normal saline with room temperature was used to irrigate surgical field. Serum ADH, and the osmolalities (serum and urine) were measured. In 6 patients, serum TSH and FSH were measured, simultaneously. Results: There were no significant hemodynamic changes during procedure. UO was decreased in 50% during and after the drilling. No differences showed in UO between before and after the drilling of CHP. Plasma ADH level after the CHP was increased 2-3 fold than before. Serum osmolality was unchanged throughout the periods, while the urine osmolality was significantly increased after the period of CHP. FSH was not changed during the periods and TSH was decreased slightly than in Pre-D. Conclusions: Ｔhe reduced urine output during mastoidectomy may be influenced by the drilling-related vibration, which may affect the supraoptico-hypophyseal tract, resulting in ADH release. The irrigated isotonic saline with higher osmolality (308 mOsm/) than plasma osmolality may partly contributed to the increased ADH.

The utility of hemoglobin based oxygen carriers (HBOC) - can animal studies help?

) on augmentation of tissue oxygenation following isovolemic hemodilution. They have determined that, in their dog model, liver tissue oxygenation can be further improved by using HBOC-201 in a situation where physiological reserves are near their limits. What are the implications of their findings for the practicing anesthesiologist?To put their findings into context, we must first review what the physiological consequences of iso-volemic hemodilution (as used in their study) are as opposed to those which occur during unresuscitated hemorrhage. In the latter, as hemorrhage progresses, hemoglobin levels fall and to preserve homeostatis, cardiac output falls and systemic vascular resistance increases. Tissue perfusion is impaired leading to increased ischemia – particularly in the splanchnic bed. The clinical picture of cool extremities and reduced urine output will be familiar to any practitioner deal-ing with trauma patients.In contrast, in the setting of isovolemic hemodilu-tion (i.e., sufficient resuscitation with crystalloids or colloids so as to maintain intravascular volume albeit with a reduced hemoglobin level), the situation is somewhat different. As demonstrated by Freitag et al.,

The use of recovery methods post‐exercise

Competitive soccer engages many of the body's systems to a major extent. The musculoskeletal, nervous, immune and metabolic systems are stressed to a point where recovery strategies post‐exercise become influential in preparing for the next match. Intense activity at a 7-day training camp causes participants to experience lowered concentrations of non-killer cells and T-helper cells. Two consecutive games in 24 h produce disturbances in the testosterone – cortisol ratio. When competitive schedules are congested, the recovery process should be optimized for performance capabilities to be restored to normal as soon as possible. There is evidence that glycogen stores are reduced near to depletion at the end of a soccer game and that a diet high in carbohydrates can aid recovery. Water alone is not the best means of restoring body fluids, since carbohydrate-electrolyte drinks display better intestinal absorption and reduce urine output. Some relief from muscle soreness may be achieved by means of a warm-down. Deep-water running regimens can replace conventional physical training in the days after competition. Massage, cryotherapy and alternative therapies have not been shown to be consistently effective. It is concluded that optimizing recovery post‐exercise depends on a combination of factors that incorporate a consideration of individual differences and lifestyle factors. The procedures to facilitate recovery processes should start immediately the game or training finishes. Match administrators and tournament planners should consider the stressful consequences for players in periods of congested fixtures and alleviate the physiological strain as far as possible by allowing 72 h between competitive games. This frequency of competition is unlikely to be sustainable in the long term.

Thrombophilia in neonatal renal venous and arterial thrombosis

Sirs, Renal venous thrombosis (RVT) is a classical disease in neonates, especially those that are preterm. It is a rare disorder with severe consequences for the affected kidney(s). A recent survey, carried out in Germany over a 2year period, identified 35 proven cases, corresponding to an incidence of 2.2 in 100,000 live births; half of these were premature [1]. Organ scarring was observed in 26 of the 39 affected kidneys. The clinical presentation consists of increased kidney size, macroor microhematuria, reduced urine output, and some degree of renal failure. Renal ultrasonography shows unior bilateral kidney enlargement with little flow and in many cases additional thrombi in the vena cava. The cause of RVT is unclear. The following predisposing factors have been identified in several earlier studies: maternal diabetes, traumatic delivery, prematurity, hyperviscosity, hypovolemia, and hemoconcentration. Recent single case observations have pointed to the association of RVT with activated protein C resistance, especially in bilateral cases [2, 3, 4, 5]. One multicenter case-control study in neonates and infants with abdominal venous thrombosis was published [6]. The odds ratio for RVT was 10.9 in infants with different forms of thrombophilia. Treatment remains controversial in the absence of trials to compare supporting therapy with anticoagulation and/or thrombolysis. Renal artery thrombosis (RAT) in the neonate is far less common than RVT, and there is little information about its incidence. It is strongly associated with umbilical catheters and patent ductus arteriosus [7]. The clinical presentation is rather silent and renal ultrasound findings can be minimal unless Doppler imaging is used. The outcome of the affected kidneys is poor with global atrophy being the rule. To the best of our knowledge, no patients with neonatal RAT and thrombophilia have been reported to date. Thrombophilia is an acquired or genetic state of hypercoagulability; the most common abnormalities being genetic in origin. Established genetic forms predisposing to venous thrombosis are deficiencies of antithrombin, protein C, and protein S, mutations in the promotor of the gene encoding prothrombin and factor V Leiden mutation. Mutations in the gene for methylenetetrahydofolate reductase, which lead to hyperhomocysteinemia, are associated with venous as well as arterial thrombosis. Over the last 25 years, ten patients were followed regularly in our Renal Unit for renal damage as a consequence of renal venous or arterial thrombosis in the neonatal period. There were eight boys and two girls. RVT was diagnosed in five patients, of whom two had bilateral thrombosis. RAT was observed in another five patients and was unilateral in all. The diagnosis of RVT was based on clinical, laboratory, and ultrasound manifestations. All patients had hematuria, thrombocytopenia, and kidney enlargement. The diagnosis of RAT was based on arterial hypertension, reduced kidney size, and poor renal perfusion. The two patients with bilateral RVT developed chronic renal failure. Of the five patients with RAT, three have complete atrophy of the affected kidney and two with a remnant kidney have needed antihypertensive drugs for several years. The investigations for thrombophilia were performed when the patients were aged between 18 months and 22 years. In two patients W. Proesmans · P. van de Wijdeven Renal Unit, Department of Pediatrics, University Hospital, Leuven, Belgium

The hemodynamic and neurohormonal effects of low doses of tezosentan (an endothelin A/B receptor antagonist) in patients with acute heart failure

In previous studies (the RITZ project), tezosentan, an intravenous (i.v.)-balanced dual endothelin (ET-A/B) antagonist, in doses of 50 and 100 mg/h, improved the hemodynamics but not the clinical outcome of patients with acute heart failure (AHF). To evaluate the effect of lower doses of tezosentan in patients with AHF. Included were 130 patients hospitalized due to AHF with dyspnea at rest, despite initial treatment, and were in need of hemodynamic monitoring with cardiac index (CI)<2.5 l/min/m(2) and wedge pressure > or = 20 mm Hg. Patients were randomized in a double-blind fashion to receive placebo or tezosentan: 0.2, 1, 5, or 25 mg/h for 24 h. The primary endpoint of the study, CI increase at 6 h of treatment, was significant in the 5 and 25 mg/h groups. Tezosentan induced a dose-dependent increase in CI and a decrease in wedge pressure, peaking after 3 h in the 5 and 25 mg/h groups. In the 1 mg/h group, this effect was smaller during the first 6 h and increased gradually, becoming significant at 24 h and beyond treatment discontinuation. There was no hemodynamic effect in the 0.2 mg/h arm. Type-B natriuretic peptide (BNP) decreased in the 1, 5, and 25 mg/h groups but not on placebo. Endothelin levels were significantly increased by the 5 and 25 mg/h groups but not in the lower (< or = 1 mg/h) tezosentan doses. Urine output decreased on the 25 mg/h dose. There was a trend towards improvement in patients' subjective dyspnea score and worsening heart failure events, mainly in the 1 mg/h group. In patients admitted with AHF, tezosentan doses of 1-25 mg/h are efficacious in improving the hemodynamics and reducing BNP. Tezosentan doses beyond 1 mg/h increased plasma endothelin levels and reduced urine output, probably limiting their clinical efficacy, as compared to tezosentan 1 mg/h.

THE CIRCADIAN RHYTHM OF URINE PRODUCTION, AND URINARY VASOPRESSIN AND PROSTAGLANDIN E2 EXCRETION IN HEALTHY CHILDREN

In adults and adolescents the transition from day to night is followed by a pronounced decrease in diuresis, as well as reduction in the amount of osmotically active substances excreted. We investigate the circadian variations in urine production in healthy children 3 to 14 years old. A total of 92 children completed urine collections in 2 consecutive days to be analyzed for electrolytes, urea, creatinine, osmolality, vasopressin and prostaglandin E2. We found a marked reduction in urine output during the night (43.41 +/- 18.53 to 25.69 +/- 12.71 ml per hour) accompanied by a decrease in the amount of electrolytes excreted (sodium 4.44 +/- 2.09 to 2.66 +/- 1.55 mmol per hour and potassium 2.38 +/-0.96 to 0.90 +/- 0.54 mmol per hour). Age and gender did not influence the observed circadian rhythm in the quantity and quality of urine production. Urinary excretion of vasopressin did not seem to reflect the circadian variations previously described for the plasma levels of the hormone. Prostaglandin E2 showed a clear circadian variation with a 30% decrease at night (32.2 +/- 19.0 to 22.0 +/- 12.6 ng/mmol creatinine). Healthy children exhibit pronounced circadian variations in the amount and composition of urine output with a decrease in nocturnal diuresis and excretion of osmotically active solutes. In the age range of 3 to 14 years neither age nor gender seems to affect this rhythm. Vasopressin-to-prostaglandin E2 excretion ratio appears to be of importance for regulation of urine production.