Reduced Urine Output Research Articles

Amiodarone-induced acute hepatotoxicity

Dear Editor, We present the case of a 44-year-old man admitted with central chest pain associated with breathlessness that was not relieved by taking sublingual glyceryl nitrate. He presented with a background of old inferior infarct, dilated cardiomyopathy and poor left-ventricular (LV) function and hypertension. There was history of continued alcohol and cocaine abuse. Electrocardiogram on admission confirmed atrial flutter, ventricular rate of 160 bpm with evidence of heart failure, and systolic blood pressure 90 mmHg. All biochemical and hematological parameters were within normal limits. Intravenous (IV) amiodarone 300 mg was administered intravenous (i.v) over 30 min and a maintenance dose of 900 mg over 24 h to attempt pharmacological cardioversion. His heart rate slowed down and later reverted to sinus rhythm. However, over night, he became transiently hypotensive with reduced urine output that subsequently improved. Repeat blood tests the following day revealed an acute increase in alanine aminotransferase (ALT) to 4,428 (see Table 1) and bilirubin to 45. Amiodarone was discontinued. ALT peaked at 4,578 on day 3 but returned to normal at day10. Hepatic ultrasound revealed no abnormality. In particular, there was no evidence of hepatic congestion. The patient was started on digoxin, anti-heart-failure medication optimized his condition, and once he was stable. He was discharged with a further cardiology follow-up. Discussion

Urocortin 2 sustains haemodynamic and renal function during introduction of beta-blockade in experimental heart failure

The challenge in management of acute decompensated heart failure (ADHF) is relieving congestion and improving symptoms while preserving renal and systemic perfusion at a level that can tolerate introduction of drugs such as beta-blockers which may have adverse effects acutely yet have proven benefit in the longer term. Urocortin 2 (Ucn2) is a novel peptide with therapeutic potential in heart failure. The present study investigated the effects of combined Ucn2 and beta-blockade in heart failure. Ucn2 and metoprolol were administered for 3 h, separately and together, in eight sheep with pacing-induced congestive heart failure. Compared with time-matched controls, metoprolol significantly reduced heart rate (HR), left ventricular contractility, cardiac output (CO) and mean arterial pressure (MAP), together with increases in peripheral resistance and left atrial pressure (LAP). In contrast, Ucn2 elevated HR, contractility, CO and MAP, and decreased peripheral resistance and LAP. Combined Ucn2 + metoprolol produced intermediate haemodynamic effects closer to those observed with Ucn2 than with beta-blockade. All three active treatment regimes decreased plasma renin activity, whereas only Ucn2 and Ucn2 + metoprolol significantly reduced plasma aldosterone. Compared with metoprolol alone (which tended to reduce urine output and creatinine excretion/clearance), Ucn2 + metoprolol increased urine volume, sodium and creatinine excretion and clearance. Ucn2 coupled with beta-blockade in experimental heart failure improves CO and MAP, sustains HR, reduces peripheral resistance, LAP and aldosterone and augments renal function. These results suggest a role for Ucn2 as a short-term parenteral therapy in the initial stages of managing ADHF that improves tolerance to introduction of beta-blockers.

Is Extracellular Volume Expansion of Peritoneal Dialysis Patients Associated with Greater Urine Output?

Background and Objectives: Residual renal function (RRF) is important for peritoneal dialysis (PD) technique failure and patient survival. Reduction in extracellular water (ECW) has been reported to reduce urine output. We audited volume status and RRF to determine whether ECW was linked to urinary output. Methods: We retrospectively audited PD patients who had RRF and multiple frequency bioimpedance spectroscopy assessments. Results: 550 patients were studied. Urine output was lower in males (p = 0.021), non-Caucasoids (p = 0.04), those prescribed antihypertensives (p < 0.001), and greater glucose dialysate usage (p < 0.001). Urine output was negatively associated with dialysis vintage (F = 40.7, β –0.627, p < 0.001), and ECW (F = 33.7, β –0.177, p < 0.001) and positively associated with intracellular volume (F = 34.6, β 0.11, p < 0.001). Conclusions: RRF is important for successful PD, and ECW volume expansion may lead to better preservation of RRF in PD patients compared to haemodialysis. However, in our retrospective cross-sectional study, ECW expansion was associated with reduced urine output.

Sepsis, Kidney, and Tissue Oxygenation

Sepsis, Kidney, and Tissue Oxygenation

Diabetic Women with Fever and Right Flank Pain

A 61 years old woman with type II diabetes mellitus presented with fever, dysuria, reduced urine output and right flank pain since 5 days, not responding to treatment. There was no history of obstructive lower urinary tract symptoms, hematuria, or trauma. On examination, there was tenderness in the right flank. Laboratory tests revealed a white blood cell count (WBC) of 18,500/mm3 with 81% neutrophils, hemoglobin concentration of 9.7 g/dl, platelet count of 15,010/mm, creatinine level of 3.1 mg/dl and urea concentration of 118 mg/dl. Urine analysis demonstrated a 20-25 WBC per high power field. Urine culture showed more than 105 colony-forming units (CFU) per mL of Escherichia coli (E.coli) sensitive to amikacin, ceftriaxone, ofloxacin, nitrofurantoin and trimethoprim. The patient’s abdominal X-ray is shown in Fig 1. Figure 1 Abdominal X-ray supine view showing RENIFORM shape collection of gas in right renal fossa (arrow).

The effects of isoflurane anesthesia and mechanical ventilation on renal function during endotoxemia

Isoflurane is a common anesthetic agent used in human surgery and in animal models of sepsis. It has been suggested to have beneficial anti-inflammatory properties and to protect kidney function. Here, we investigated the effect of isoflurane on the development of kidney injury and dysfunction during 48-h endotoxemia in sheep. Before the experiments, the sheep (n=16) were surgically equipped with transit-time flowprobes around the renal, femoral and superior mesenteric artery. The animals were randomized to either be anesthetized with isoflurane and mechanically ventilated or to remain conscious while they received intravenous Escherichia coli lipopolysaccharide (LPS) for 48 h (25 ng/kg/min). In two animals in each group, the LPS was excluded to investigate any effect of isoflurane per se over time. Endotoxemia caused cardiovascular changes typical for hyperdynamic sepsis and, although renal hyperemia occurred, impaired renal function in both groups. Compared with conscious animals, isoflurane significantly (P<0.05) reduced urine output, renal creatinine clearance, fractional sodium excretion and renal blood flow during endotoxemia. Furthermore, the plasma concentrations of urea and creatinine increased more in the anesthetized animals. Isoflurane anesthesia also enhanced neutrophil activity and accumulation in the kidney during endotoxemia. N-acetyl-β-D-glucosaminidase was significantly increased, with no inter-group difference as an indication of tubular injury. The results of the current study suggest that isoflurane anesthesia (minimum alveolar concentration 1.0) with mechanical ventilation aggravates renal dysfunction during 48 h of endotoxemia and does not significantly reduce the inflammatory response or signs of tubular damage.

Study comparing the clinical profile of complicated cases of Plasmodium falciparum malaria among adults and children

Objective To compare the clinical profile of Plasmodium falciparum (P. falciparum) malaria in adults and children. Methods In this retrospective study, data were collected from case records of patients admitted with P. falciparum malaria to the paediatric and adult critical care facility of a tertiary care hospital in an endemic area. A total of 20 adults and children were compared for their symptoms. Results In this study, among all adults and children with P. falciparum malaria, the commonest symptom was fever with chills and rigors. Among children, the next common symptoms were altered sensorium and irritability. Nine children (45%) had cerebral malaria, among which five had seizures. Other common manifestations were reduced urine output (35%) and vomiting (35%). Among adults, vomiting (65%) was the most common symptom followed by headache (60%). Eight (40%) adults had jaundice while nine (45%) had complaints of decreased urine output. Among adults, 4 had altered sensorium, of which 2 had seizures and jaundice; and all 4 had renal impairment. Conclusions Clinical symptoms and profile of P. falciparum malaria differ among age groups. Early recognition of symptoms and treatment of malaria is paramount especially in children who tend to have higher rates of complications compared to adults.

Delayed retroperitoneal bleeding causing acute abdominal compartment syndrome

Delayed acute abdominal compartment syndrome (ACS) due to retroperitoneal bleeding is rare. Herein, we report the clinical management of such a rare case. A 46-year-old male who fell from a height of 12 meters was admitted to Al-Ain Hospital. He was hemodynamically stable. His abdomen was soft and not distended. Abdominal computed tomography (CT) was normal on admission. On day 7, the patient tolerated enteral feeding. On day 15, he became suddenly hypotensive. CT of the abdomen showed a large retroperitoneal hematoma compressing the inferior vena cava (IVC) associated with contrast blush indicating active bleeding. The abdomen became distended and tense. The patient developed respiratory failure and severe acidosis, increased airway pressure and reduced urine output. A clinical diagnosis of ACS was made. There was dramatic improvement in the hemodynamic and respiratory function directly after laparotomy. Exploration of the retroperitoneal hematoma showed an actively bleeding ligated ileocolic vessel. The abdomen was temporarily closed using saline IV bags sandwiched between two layers of Steri-Drape. The abdomen was closed primarily on day 6. The patient was discharged home on day 50. Life-threatening delayed retroperitoneal bleeding may occur suddenly two weeks after trauma causing ACS.

The Effects of Dietary Protein Content and Manure Handling Technique on Ammonia Emissions During Short-Term Storage of Dairy Cow Manure

An improved understanding of the potential for dietary protein manipulation to reduce ammonia emissions from dairy farms during various stages of manure handling is needed for both modeling and policy-making efforts. The objective of this study was to assess the effects of dietary protein manipulation on ammonia emissions from relatively freshly voided dairy cow manure in three types of removal systems: scraped manure removal systems, flushed manure removal systems, and flushed manure removal systems with a solids separator. Emissions were measured using a dynamic flux chamber for 12 h or more. Ammonia fluxes and emission factors per mass of manure were not affected by dietary protein content because fluxes depended mainly on total ammoniacal nitrogen (TAN) concentration, which did not vary with diet. However, emissions on a per-cow basis were 12% lower with the diet containing 15.0% crude protein as compared to the one with 17.8% (a change in crude protein of 16%) due to reduced urine output. The largest absolute impact of dietary protein manipulation would be with separated liquids because their emission factor was approximately four times higher than for the other types of manure. While dietary protein manipulation can reduce ammonia emissions from manure during long-term storage, its effectiveness in the hours immediately after manure is excreted is limited because emissions are more sensitive to other factors, including temperature and extent of mixing of the manure, that vary widely under real operating conditions on a farm.

Pretransplant Predictors and Posttransplant Sequels of Acute Kidney Injury after Allogeneic Stem Cell Transplantation

Acute kidney injury (AKI) is a common complication after allogeneic stem cell transplantation (SCT). Although various risk factors for AKI have been reported, the influence of pretransplant comorbidity on the incidence of AKI has not been well investigated. We performed a retrospective analysis of 207 consecutive patients undergoing myeloablative or nonmyeloablative SCT between 2001 and 2009, using the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) as a representative of pretransplant comorbidities. According to Risk, Injury, Failure, Loss, and End-stage kidney disease (RIFLE) criteria, 158 patients (76.3%) developed AKI, and 92 patients (44.4%) developed severe AKI (RIFLE class I or class F) within 100 days after SCT. The cumulative incidence of severe AKI within 100 days in patients with an HCT-CI score 0, 1-2, and ≥3 was 21.3%, 48.8%, and 73.9%, respectively. In multivariate analysis, the HCT-CI was independently associated with severe AKI (HCT-CI 1-2: adjusted hazard ratio [HR] 2.42, P < .01; HCT-CI ≥3: adjusted HR 4.69, P < .01). In a landmark analysis, patients with severe AKI had a lower 3-year overall survival (OS) (39.3% versus 61.4%, P < .01), and a higher 3-year nonrelapse mortality (NRM) (40.8% versus 5.6%, P < .01) than those without AKI. Multivariate analysis showed that severe AKI was a significant risk factor for worse OS (HR: 2.10, P = .01) and NRM (HR: 6.15, P < .01). Thus, it is important to assess the HCT-CI to predict the incidence of AKI, which is a strong indicator of worse prognosis after SCT.

Cyclooxygenase 2 inhibition exacerbates AQP2 and pAQP2 downregulation independently of V2 receptor abundance in the postobstructed kidney

Previously we demonstrated that ANG II receptor (AT1R) blockade attenuates V2 receptor (V2R), AQP2, and pS256-AQP2 downregulation in the postobstructed kidney and partially reverses obstruction-induced inhibition of cAMP generation and cyclooxygenase 2 (COX-2) induction. Therefore, we speculated whether the effects of AT1R blockade on V2R and the vasopressin-regulated pathway are attributable to attenuated COX-2 induction. To examine this, rats were subjected to 24-h bilateral ureteral obstruction (BUO) followed by 48-h release and treated with the COX-2 inhibitor parecoxib or saline. Control rats were sham-operated. Parecoxib treatment significantly reduced urine output 24 h after release of BUO whereas urine osmolality and solute-free water reabsorption was comparable between saline- and parecoxib-treated BUO rats. Immunoblotting revealed a significant decrease in AQP2 and pS256-AQP2 abundance to 20 and 23% of sham levels in parecoxib-treated BUO rats compared with 40 and 55% of sham levels in saline-treated BUO rats. Immunohistochemistry confirmed the exacerbated AQP2 and pS256-AQP2 downregulation in parecoxib-treated BUO rats. Finally, parecoxib treatment had no effect on V2R downregulation and the inhibited, vasopressin-stimulated cAMP generation in inner medullary membrane fractions from the postobstructed kidney. In conclusion, COX-2 inhibition exacerbates AQP2 and pS256-AQP2 downregulation 48 h after release of 24-h BUO independently of V2R abundance and vasopressin-stimulated cAMP generation. The results indicate that COX-2 inhibition does not mimic AT1R blockade-mediated effects and that AT1R-mediated AQP2 regulation in the postobstructed kidney collecting duct is independent of COX-2 induction.

Aggressive approach in a case of cancer cervix with uremia

Carcinoma of cervix is the most common cancer in developing countries. Majority of them present in locally advanced stages. A 36-year-old lady presented with bleeding and white discharge per vagina since four months, vomiting and reduced urine output since two weeks. Patient had an exophytic cervical growth. Investigation revealed elevated serum creatinine. Patient received single fraction radiation and underwent percutaneous nephrostomy. At one month follow-up, serum creatinine returned to almost normal level. Patient underwent bilateral ante grade stenting and completed concurrent chemoradiotherapy. In selected subsets of patients, aggressive management offered longer palliation and good quality of life.

Plasma neutrophil gelatinase-associated lipocalin is an early biomarker for acute kidney injury in an adult ICU population

PurposeNeutrophil gelatinase-associated lipocalin (NGAL) is a useful marker for acute kidney injury (AKI), particularly when the timing of renal insult is known. However, its performance in an adult critical care setting has not been well described. We performed this study to estimate the diagnostic accuracy of plasma NGAL for early detection of AKI and need for renal replacement therapy (RRT) in an adult intensive care unit (ICU).MethodsWe enrolled 307 consecutive adult patients admitted to a general medical-surgical ICU; 301 were included in the final analysis. Serial blood samples were analyzed for plasma NGAL using a standardized clinical platform. The primary outcome was AKI, defined as an increase in creatinine of at least 50% from baseline or a reduction in urine output to <0.5 ml/kg/h for >6 h.ResultsOf 301 patients, 133 (44%) had AKI during their ICU stay. Plasma NGAL was a good diagnostic marker for AKI development within the next 48 h (area under ROC 0.78, 95% CI 0.65–0.90), and for RRT use (area under ROC 0.82, 95% CI 0.70–0.95). Peak plasma NGAL concentrations increased with worsening AKI severity (R = 0.554, P < 0.001).ConclusionsPlasma NGAL is a useful early marker for AKI in a heterogeneous adult ICU population, in which the timing of renal insult is largely unknown. It allows the diagnosis of AKI up to 48 h prior to a clinical diagnosis based on AKI consensus definitions. Additionally, it predicts need for RRT and correlates with AKI severity. Early identification of high risk patients may allow potentially beneficial therapies to be initiated early in the disease process before irreversible injury occurs.Electronic supplementary materialThe online version of this article (doi:10.1007/s00134-009-1711-1) contains supplementary material, which is available to authorized users.

Female Infant With Fever and Rash

An 18-month-old girl with an unremarkable birth history presented to our pediatric emergency department with a fever and rash that began the previous day. The patient's mother stated that the patient also had decreased oral intake, reduced urine output, and 2 episodes of nonbloody nonbilious emesis. Her vital signs included a pulse rate of 185 beats/min, respiratory rate of 43 breaths/min, blood pressure of 88/42 mmHg, oxygen saturation of 95% on room air, and a rectal temperature of 38.7°C (101.6°F).

Effects Of Electrolytes In Drinks Ingested Before And During Cycling Time Trials

PURPOSE: To determine whether the addition of electrolytes to drinks consumed before and during exercise improves cycling time trial performance. METHODS: Healthy, active males (n=7; mean age=38.8±5.1 years, weight=75.1± 6.1 kg, %fat=12.7±5.3%, OBLA=215 ±38 Watts) participated in 4 randomly ordered conditions combining 1 of 2 pre-exercise drink formulations with 1 of 2 during-exercise drink formulations. Each condition consisted of a 2-h drinking phase followed immediately by a cycling time trial designed to last ∼90-min. The 2 pre-exercise drinks (13-ml/kg BW) were either (W) flavored water or (E) flavored water containing 9.62 g/L of Gatorlytes electrolyte mixture (Na=2.18 g/L, K=1.10 g/L, Osm=300 mOsm/L). The during-exercise drinks (17-ml/kg BW) were either (w) a 6% carbohydrate beverage or (e) a 6% carbohydrate beverage plus electrolytes (Na =0.83 grams/L, K=0.375g/L). Thus, the 4 conditions were Ww, We, Ew, and Ee, which were tested using 1-way ANOVA for effects on primary outcomes of time-trial performance, fluid balance and change in relative plasma volume (PV). RESULTS: Urine rates during the drinking phase were higher for Ww and We (9.43± 3.15 ml/min) than for Ew and Ee (5.98±ml/min) leading to a greater positive fluid balance (input - output) for Ew and Ee (+199± 280ml) vs. Ww and We (-109±365 ml). Fluid balance differences were largely attributed to disparity in urinary free water clearance between Ew and Ee (0.5±1.8 ml/min) vs. Ww and We (4.2±2.3 ml/min). Change in PV from blood samples taken before and after the drinking phase was greater for Ew and Ee (1.5±10.0 ml) than for Ww and We (-4.6±6.9 ml). This difference in PV was not assoc. with s.d's. in HR, SV, CO or BP. Cycling time was slower (p<0.05) for Ww (90.1± 6.0 min) compared to times for Ew (85.4±6.2 min), We (87.0±5.7 min) and Ee (87.6±6.2 min), which were not different among each other (p>0.05). CONCLUSION: Pre-exercise administration of a drink containing a 300 mOsm/L electrolyte mixture caused a reduction in urine output leading to a higher fluid balance and PV. Cycling time trial performance lasting ∼90-min was improved in conditions where electrolytes were added to the drink either before or during exercise but there was no additional improvement in performance when electrolytes were added to both the before and during-exercise drinks.

Anti-Inflammatory and Renal Protective Actions of Stanniocalcin-1 in a Model of Anti-Glomerular Basement Membrane Glomerulonephritis

We have previously shown that stanniocalcin-1 (STC1) inhibits the transendothelial migration of macrophages and T cells, suppresses superoxide generation in macrophages, and attenuates macrophage responses to chemoattractants. To study the effects of STC1 on inflammation, in this study we induced a macrophage- and T-cell-mediated model of anti-glomerular basement membrane disease in STC1 transgenic mice, which display elevated serum STC1 levels and preferentially express STC1 in both endothelial cells and macrophages. We examined the following parameters both at baseline and after anti-glomerular basement membrane antibody treatment: blood pressure; C(3a) levels; urine output; proteinuria; blood urea nitrogen; and kidney C(3) deposition, fibrosis, histological changes, cytokine expression, and number of T cells and macrophages. Compared with wild-type mice, after anti-glomerular basement membrane treatment STC1 transgenic mice exhibited: i) diminished infiltration of inflammatory macrophages in the glomeruli; ii) marked reduction in crescent formation and sclerotic glomeruli; iii) decreased interstitial fibrosis; iv) preservation of kidney function and lower blood pressure; v) diminished C(3) deposition in the glomeruli; and vi) reduced expression of macrophage inhibitory protein-2 and transforming growth factor-beta2 in the kidney. Compared with baseline, wild-type mice, but not STC1 transgenic mice, had higher proteinuria and a marked reduction in urine output. STC1 had minimal effects, however, on both T-cell number in the glomeruli and interstitium and on cytokine expression characteristic of either TH1 or TH2 activation. These data suggest that STC1 is a potent anti-inflammatory and renal protective protein.

A case of nephrogenic diabetes insipidus caused by partial bilateral ureteral obstruction due to advanced stage ovarian carcinoma

Nephrogenic diabetes insipidus (NDI) secondary to chronic urinary tract obstruction is a rare condition. The exact cause is unknown; it is likely that increased collecting duct pressures cause damage to the tubular epithelium, resulting in insensitivity to the antidiuretic hormone (ADH). We report a case of NDI associated with ureteral obstruction caused by advanced stage ovarian carcioma in a 20-year-old girl. After debulcking surgery, massive polyuria continued. Several administrations of an ADH analog were ineffective in reducing urine output, suggesting a possible relationship of massive polyuria with NDI. Following oral administration of a thiazide diuretic, known to exert antidiuretic action in NDI, the urine output was dramatically reduced. This case suggests that ureteral obstruction due to ovarian mass may cause NDI and after the surgery thiazide diuretics are effective in reducing urine output in NDI with ureteral obstruction.

Pilot safety study of low-dose vasopressin in non-septic critically ill children

To assess the safety of low-dose vasopressin infusion in critically ill children requiring prolonged mechanical ventilation (MV) at risk of developing sedation/analgesia-related hypotension. Randomized pilot safety study in children expected to require MV for at least 3 days. Children received either vasopressin (0.0005 U/kg/min) or sodium chloride (0.9%) infusion for a period of 48 h. Haemodynamic variables, urine output and serum electrolytes were closely monitored and analyzed. Twelve children in each group had similar baseline characteristics. Vasopressin infusion was associated with an 8 mmol/L fall in serum sodium concentration (p < 0.01) and with higher incidence of hyponatraemia (8 vs. 66%, p < 0.01). In normotensive children, low-dose vasopressin also induced a reversible decrease in urine output, and acutely increased blood pressure (p < 0.01). After stopping the vasopressin there was rebound hypotension (p < 0.01). Low-dose vasopressin infusion in haemodynamically stable, but critically ill, children is associated with reduction in urine output and decreased serum sodium level, yielding a high incidence of hyponatraemia. We conclude that these effects limit further study of prophylactic vasopressin for sedation-related hypotension in a randomized controlled trial.

Hydroxyethylstarch impairs renal function and induces interstitial proliferation, macrophage infiltration and tubular damage in an isolated renal perfusion model

IntroductionThe aim of the study was to evaluate some of the underlying pathomechanisms of hydroxyethylstarch (HES) induced adverse effects on renal function using 24 porcine kidneys in an isolated perfusion model over six hours.MethodsInfusion of either 10% HES 200/0.5, 6% HES 130/0.42 or Ringer's lactate (RL) was performed to achieve an haematocrit of 20% in eight kidneys from four animals per group. Physiological and pathophysiological parameters were determined (including N-acetyl-beta-aminoglucosidase as a marker for lysosomal tubular damage). Histological investigations and immunohistological stainings of the kidneys were performed.ResultsInitially after haemodilution, HES 130/0.42 and HES 200/0.5 reduced urine output compared with RL (P < 0.01). After six hours, N-acetyl-beta-aminoglucosidase was significantly higher in HES 200/0.5 (81 ± 23 U/L) compared with HES 130/0.42 (38 ± 12 U/L) and RL (21 ± 13 U/L; P < 0.001). Osmotic nephrosis-like lesions (OL) of the tubuli were present in all groups showing a significantly lower number of OL in RL (1.1 ± 0.4; P = 0.002) compared with both HES groups (HES 200/0.5 = 2.1 ± 0.6; HES 130/0.42 = 2.0 ± 0.5). Macrophage infiltration was significantly higher in HES 200/0.5 compared with HES 130/0.42 (1.3 ± 1.0 vs. 0.2 ± 0.04; P = 0.044). There was a significant increase in interstitial cell proliferation in the HES 200/0.5 group vs. HES 130/0.42 (18.0 ± 6.9 vs. 6.5 ± 1.6; P = 0.006) with no significant difference in RL (13.5 ± 4.0).ConclusionsWe observed impaired diuresis and sodium excretion by HES and identified renal interstitial proliferation, macrophage infiltration and tubular damage as potential pathological mechanisms of HES-induced adverse effects on renal function using an isolated porcine renal perfusion model. Furthermore, we demonstrated that 10% HES 200/0.5 had more of a pro-inflammatory effect compared with 6% HES 130/0.42 and caused more pronounced tubular damage than 6% HES 130/0.42 and RL. OL were present in all groups, but to a lesser degree after RL administration.

New Benzylureas as a Novel Series of Potent, Nonpeptidic Vasopressin V2 Receptor Agonists

Vasopressin (AVP) is a hormone that stimulates an increase in water permeability through activation of V2 receptors in the kidney. The analogue of AVP, desmopressin, has proven an effective drug for diseases where a reduction of urine output is desired. However, its peptidic nature limits its bioavailability. We report herein the discovery of potent, nonpeptidic, benzylurea derived agonists of the vasopressin V2 receptor. We describe substitutions on the benzyl group to give improvements in potency and subsequent modifications to the urea end group to provide improvements in solubility and increased oral efficacy in a rat model of diuresis. The lead compound 20e (VA106483) is reported for the first time and has been selected for clinical development.