ularitide and Acute-Kidney-Injury

Topics: Acute Kidney Injury; Atrial Natriuretic Factor; Diuretics; Humans; Kidney Function Tests; Peptide Fragments; Renal Replacement Therapy

Topics: Acute Kidney Injury; Atrial Natriuretic Factor; Biocompatible Materials; Calcium Channel Blockers; Diuretics; Diuretics, Osmotic; Dopamine; Evidence-Based Medicine; Growth Substances; Humans; Mannitol; Membranes, Artificial; Peptide Fragments; Renal Agents; Renal Circulation; Renal Dialysis; Renal Replacement Therapy

Natriuretic peptides (NP) constitute hormonal systems of great clinical impact. This report deals with Urodilatin (URO), a renal natriuretic peptide type A. From the gene of NP type A, a message for the preprohormone is transcribed in heart and kidney. The cardiac prohormone CDD/ANP-1-126 is synthesized in the heart atrium and processed during exocytosis forming the circulating hormone CDD/ANP-99-126. URO (CDD/ANP 95-126) is a product from the same gene, but differentially processed in the kidney and detected only in urine. Physiologically, URO acts in a paracrine fashion. After release from distal tubular kidney cells into the tubular lumen, URO binds to luminal receptors (NPR-A) in the collecting duct resulting in a cGMP-dependent signal transduction. cGMP generation is followed by an interaction with the amiloriode-sensitive sodium channel which induces diuresis and natriuresis. In this way, URO physiologically regulates fluid balance and sodium homeostasis. Moreover, URO excretion and natriuresis are in turn dependent on several physiological states, such as directly by sodium homeostasis. Pharmacologically, URO at low dose administered intravenously shows a strong diuretic and natriuretic effect and a low hypotensive effect. Renal, pulmonary, and cardiovascular effects evoked by pharmacological doses indicate that URO is a putative drug for several related diseases. Clinical trials show promising results for various clinical indications. However, the reduction in hemodialysis/hemofiltration in patients suffering from ARF following heart and liver transplantation, derived from preliminary trials recruiting a small number of patients, was not confirmed by a multicenter phase II study. In contrast, data for the prophylactic use of URO in this clinical setting suggest a better outcome for the patients. Furthermore, treatment of asthmatic patients showed a convincingly beneficial effect of URO on pulmonary function. Patients with congestive heart failure may also profit from URO treatment, as it increases stroke volume and PCWP. Moreover, preliminary results from recent studies indicate that URO may also be effective in patients suffering from hepato-renal syndrome.

Topics: Acute Kidney Injury; Amino Acid Sequence; Atrial Natriuretic Factor; Diuretics; Heart Failure; Hepatorenal Syndrome; Humans; Molecular Sequence Data; Peptide Fragments; Second Messenger Systems

Ularitide is a member of the natriuretic peptide family which is presumably synthesized in the kidney. In physiological experiments a correlation between Ularitide excretion and natriuresis has been found. Ularitide infusions and bolus injections in animals initiated profound diuresis and natriuresis as the most prominent effects. On the basis of findings in in-vitro and in-vivo experiments, Ularitide was used in clinical trials, and the results indicate that it could be a promising new drug to prevent and treat acute renal failure in patients after cardiac surgery and organ transplantation.

Topics: Acute Kidney Injury; Amino Acid Sequence; Animals; Atrial Natriuretic Factor; Cardiac Surgical Procedures; Clinical Trials as Topic; Diuretics; Humans; Kidney; Molecular Sequence Data; Muscle Proteins; Peptide Fragments; Postoperative Complications; Receptors, Atrial Natriuretic Factor; Second Messenger Systems; Transplantation; Vasodilator Agents

Cardiodilatin/atrial natriuretic peptide (CDD/ ANP) is a hormone system of great clinical importance. The prohormone CDD/ANP-1-126 is a peptide synthesized in the heart and cleaved during exocytosis into the circulating form CDD/ANP-99-126. Urodilatin (CDD/ ANP-95-126) is a homologue natriuretic peptide that differs from CDD/ANP-99-126 by four amino acids. Whereas CDD/ANP-99-126 circulates in blood plasma and is not excreted into the urine, urodilatin is detected only in urine. Urodilatin exerts its renal effects in a paracrine fashion. After its secretion from cells in the distal tubule, it interacts with luminally located receptors in the collecting duct, resulting in increased diuresis and natriuresis. Results suggest that urodilatin plays an important role in the physiologic regulation of fluid-balance and sodium homeostasis. Pharmacology studies reveal significant differences when urodilatin and CDD/ANP-99-126 are given intravenously, showing that stronger diuresis and natriuresis are induced by urodilatin as compared with those induced by CDD/ANP-99-126. Clinical studies indicate the prophylactic and therapeutic effect of urodilatin in patients suffering from acute renal failure following heart and liver transplantation. A significant reduction in requirements for hemodialysis/hemofiltration can be achieved using urodilatin. Postobstructive diuresis and natriuresis is probably due to a defective urinary concentrating mechanism and is usually resistant to treatment with antidiuretic hormone. The distal tubule and collecting duct have often been considered to be the site of altered sodium and water excretion following relief of obstruction. Since circulating CDD/ANP-99-126 levels are markedly elevated during obstruction and decrease upon relief of the obstruction, natriuretic peptides may play an important role in this clinical feature. On the basis of recent findings attributing an important role in sodium homeostasis to urodilatin in contrast to CDD/ANP-99-126, future studies have to clarify whether urodilatin, not CDD/ANP-99-126, might be responsible for the altered renal sodium excretion observed in postobstructive diuresis. In the past decade a considerable amount of research has led to the identification and characterization of hormones of the natriuretic peptide family [13]. These peptides are involved in the regulation of salt and water homeostasis. The prototype of the natriuretic hormones is cardiodilatin/atrial natriuretic peptide (CDD/ANP)

Topics: Acute Kidney Injury; Atrial Natriuretic Factor; Diuretics; Humans; Peptide Fragments; Protein Precursors; Receptors, Atrial Natriuretic Factor; Second Messenger Systems; Vasodilator Agents

Topics: Acute Kidney Injury; Amino Acid Sequence; Animals; Asthma; Atrial Natriuretic Factor; Bronchodilator Agents; Heart Failure; Humans; Lung; Molecular Sequence Data; Neuropeptides; Peptide Fragments; Pituitary Adenylate Cyclase-Activating Polypeptide; Vasoactive Intestinal Peptide; Vasodilator Agents

On the subject of natriuretic peptides there is a great deal of controversy, and intensive research efforts have been made studying their effects on electrolyte homeostasis. In the early 1980s, a peptide that caused diuresis, natriuresis, and had a relaxant effect on vascular smooth muscle was discovered independently by several groups. This was the breakthrough for the identification of natriuretic peptides, followed by the characterisation of the amino-acid sequences of several species. Synthesis of the peptide, cloning of the encoding gene, identification and characterisation of specific receptors, as well as the development of antibodies and radioimmuno-assays were rapidly accomplished. Research on the immunohistochemistry of cardiodilatin/atrial natriuretic peptide (CDD/ANP) and the regulation of CDD/ANP gene expression led to detection of the peptide in extra-atrial tissues. Later on, two new peptides were discovered brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). These peptides share structural features with CDD/ANP with regard to their 17-amino-acid-exhibiting loop bridged by a disulfide bond. Another recently discovered peptide is urodilatin (URO), a renal-borne new member of A-type natriuretic peptide. URO was isolated from human urine and consists of the same sequence as CDD/ANP, containing the 17-amino-acid residue loop of the circulating hormone with 4 additional amino acids located at the NH2-terminus of the peptide. Regarding physiological actions, data strongly support a close association between URO and urinary sodium excretion. The application of URO in animals revealed a stronger diuresis and natriuresis with a lower influence on arterial blood pressure compared to CDD/ANP-99-126. These results were encouraging for the use of URO in clinical trials as a tool to prevent acute renal failure (ARF) in patients following heart transplantation and for treatment of incipient ARF in patients following liver transplantation. Summarising the results of these two studies, URO represents a new approach for not only prevention, but also for treatment of ARF following organ transplantation. This opens up new possibilities for the treatment of ARF of other origins in intensive care medicine.

Topics: Acute Kidney Injury; Amino Acid Sequence; Atrial Natriuretic Factor; Critical Care; Diuretics; Humans; Molecular Sequence Data; Peptide Fragments

The characterization of a complex cerebrocardio-renal axis responsible for fluid and electrolyte homeostasis, with the isolation and identification of natriuretic peptides, has provided a potential therapeutic window into a condition associated with high morbidity and mortality in the ICU--acute renal failure (ARF). The potent natriuretic, diuretic, and renovascular actions of this family of peptides directly challenge the pathologic aberration in intrarenal hemodynamic and tubular function characterized by this condition. Unfortunately, human studies have not shown atrial natriuretic peptide to be the panacea as animal studies originally suggested. However, studies were clouded by the impact of polypharmacy, multisystem pathology, the timing of intervention, and the lack of any clear dose-response relationship for these peptides. Nonetheless, hormonal manipulation of physiologic aberration remains a potential therapeutic reality with ongoing isolation and understanding of new peptides, such as urodilatin, which may yet impact upon the treatment and outcome of ARF in the near future.

Topics: Acute Kidney Injury; Animals; Atrial Natriuretic Factor; Bias; Clinical Trials as Topic; Diuretics; Drug Evaluation, Preclinical; Humans; Peptide Fragments

Ularitide is a member of the natriuretic peptide family. This hormone exhibits an N-terminal extension by four amino acids compared with atrial natriuretic peptide. Ularitide was shown to exert strong diuretic and natriuretic effects when infused intravenously. Its main action sites are the glomerulum, inducing preglomerular vasodilation and postglomerular vasoconstriction and thereby elevating the glomerular filtration rate, and the tubular system inhibiting Na(+)-reabsorption. In initial uncontrolled clinical trials, this peptide was shown to have beneficial effects in patients suffering from oliguric acute renal failure.. We conducted a double-blind, placebo-controlled, multicenter, dose-finding trial recruiting 176 patients randomized into 4 different Ularitide doses groups (U5, U20, U40, and U80 ng/kg/min) and a placebo group (U0). Ularitide/placebo infusion was performed for 5 days with half the originally infused dose on day 5. The primary objective of the study was to test various doses of Ularitide in patients suffering from oliguric acute renal failure to avoid mechanical renal replacement therapy during the first 12 hours.. The results indicate that Ularitide does not reduce the incidence of mechanical renal replacement therapy compared with placebo-treated patients during the first 12 h of treatment (U0: 36 (20), U5: 35 (11), U20: 36 (9), U40: 28 (8), U80: 41 (12), (% (n) (p = 0.87)). Diuresis increased in the Ularitide-treated groups and the placebo group after onset of infusion and did not show any significant difference in the first 12 h collection period (U0: 576, U5: 514, U20: 500, U40: 360, U80: 158 ML/12h (Median), (p = 0.16)).. In summary, the incidence of mechanical renal replacement therapy in critically ill patients suffering from oliguric acute renal failure could not be altered positively by Ularitide administration according to our protocol. Further prospective clinical trials are needed to answer the question whether a different patient collective or a prophylactic administration of Ularitide are more promising approaches in the clinical setting of oliguric acute renal failure.

Topics: Acute Kidney Injury; Aged; Atrial Natriuretic Factor; Blood Pressure; Blood Urea Nitrogen; Cardiovascular Diseases; Creatinine; Diuretics; Double-Blind Method; Female; Humans; Hypotension; Male; Middle Aged; Peptide Fragments; Renal Replacement Therapy; Time Factors

Acute renal failure after major abdominal surgery is a severe complication in critically ill patients in intensive care units (ICU). The aim of the study was to investigate the effect of urodilatin on the peak value and course of serum creatinine in patients with acute renal insufficiency after major abdominal surgery and the necessity of apparatus-based renal replacement treatment. Furthermore, the incidence and nature of adverse events under urodilatin was documented. In a prospective randomized double-blind placebo-controlled study, 12 critically ill patients after major abdominal surgery with acute renal failure in an intensive care unit (ICU) received 20 ng/kg b.w./min urodilatin (ularitide, INN) or placebo in addition to the standard diuretic therapy or low-dose dopamine (2.5 micrograms/kg b.w./min) and furosemide (1000 mg/24 hr) for a minimum of 96 hours. All patients received mechanical ventilation. Both groups had similar serum creatinine values on the day before the onset of urodilatin/placebo infusion (2.80 +/- 0.24 mg/dl, 2.93 +/- 0.48 mg/dl). Peak serum creatinine was lower in the urodilatin group (4.65 +/- 0.57 mg/dl) compared to vehicle treatment (5.78 +/- 1.58 mg/dl), although the difference did not reach statistical significance (P = 0.148). The total number of hemodialyses due to oligo-/anuria and/or hyperkalemia was the same in both groups during the study. In 4 patients of the placebo group, diuresis was reduced to anuria, whereas only 1 of the patients treated with urodilatin became anuric. No hemodynamic side effects or adverse events due to urodilatin were observed. This clinical study under double blind conditions revealed that the addition of urodilatin to the standard diuretic therapy of low-dose dopamine and furosemide failed to improve renal function in patients with established acute renal failure and that urodilatin did not eliminate the need for apparatus-based renal replacement treatment.

Topics: Abdomen; Acute Kidney Injury; Adult; Aged; Atrial Natriuretic Factor; Critical Care; Diuretics; Dopamine; Double-Blind Method; Drug Therapy, Combination; Female; Furosemide; Humans; Kidney Function Tests; Male; Middle Aged; Peptide Fragments; Postoperative Complications; Prospective Studies; Renal Replacement Therapy; Treatment Failure

Urodilatin (URO) is a natriuretic peptide isolated from human urine which is thought to be produced by distal tubular cells. We measured urinary URO excretion in 50 healthy children and 23 children with acute (ARF), chronic renal failure (CRF), or hereditary tubular disorders, using a specific radioimmunoassay. The mean URO excreted in these four groups was 56, 45, 94, and 121 fmol/min per 1.73 m2, respectively (differences between first three groups not significant). The variation in URO excretion was larger in patients with kidney disease than in controls. There were significant correlations between urinary URO and sodium excretion in controls and CRF, but not in ARF. URO excretion also correlated with urine flow rate in CRF. Although no correlation was found between URO excretion and creatinine clearance, urinary URO was increased in some patients with advanced CRF, which suggests stimulated tubular production to compensate for reduced sodium excretion. In view of the therapeutic potential of URO in renal insufficiency, further study of the renal handling of URO is warranted.

Topics: Acute Kidney Injury; Adolescent; Atrial Natriuretic Factor; Child; Child, Preschool; Female; Humans; Kidney Diseases; Kidney Failure, Chronic; Male; Osmolar Concentration; Peptide Fragments; Reference Values; Sodium

1. Acute renal failure is a severe complication following major cardiac surgery. 2. The effects of urodilatin were evaluated in a randomized, double-blind trial in patients suffering from incipient acute renal failure following cardiac surgery. 3. In the urodilatin group (n = 7) acute renal failure was reverted, whereas in the placebo group (n = 7) six patients had to be haemofiltered or haemodialysed (P < 0.005). 4. Urodilatin induced a rapid onset of diuresis in contrast to placebo-treated patients, who remained oliguric. 5. In the placebo group four of seven patients died while still on haemodialysis (mortality rate 57.1%) during a postoperative follow-up period of 60 days, while all patients treated with urodilatin survived. 6. On the basis of these results it would appear that urodilatin is an effective drug for the treatment of incipient oliguric acute renal failure following cardiac surgery and for avoiding haemodialysis/haemofiltration.

Topics: Acute Kidney Injury; Adult; Aged; Atrial Natriuretic Factor; Cardiac Surgical Procedures; Diuretics; Double-Blind Method; Humans; Middle Aged; Peptide Fragments; Postoperative Complications; Treatment Outcome

Acute renal failure (ARF) is a serious complication following liver transplantation. Many therapeutic regimens have been used so far but with limited success. Urodilatin (URO) is a new member of the atrial natriuretic peptide (ANP) family. When administered intravenously, URO induces strong diuresis and natriuresis with tolerable hemodynamic side effects. Preliminary non-controlled clinical studies demonstrate beneficial effects using URO as a therapeutic agent in patients suffering from ARF following heart and liver transplantation (HTx, LTx). These results prompted us to initiate this first controlled clinical trial to investigate whether URO infusion can improve renal function in patients with emerging ARF following LTx.. We initiated a randomized, double-blind, placebo-controlled study comparing five patients receiving i.v. URO infusion (20 ng/kg bw/min) with four placebo patients after informed consent was obtained. Optional inclusion criteria were oliguria/anuria ( < 0.5 ml/kg/h), refractory to conventional treatment including administration of furosemide and dopamine, increase of serum creatinine to a least 200% of preoperative values, and BUN levels > or = 25 mmol/l. The primary parameters for efficacy was the frequency of hemodialysis/hemofiltration.. The frequency of hemodialysis/hemofiltration during URO or placebo infusion was significantly reduced (P = 0.03) in the URO-treated patients in comparison with placebo. BUN levels did not differ between two groups, but serum creatinine levels were consistently lower in the URO group. Diuresis tended to be stronger in the URO group, maintaining high levels despite a significant reduction in the administration of furosemide in comparison with placebo.. We conclude that URO seems to be a new approach for the treatment of therapy-resistant postoperative ARF following LTx.

Topics: Acute Kidney Injury; Adult; Aged; Atrial Natriuretic Factor; Diuresis; Diuretics; Double-Blind Method; Female; Humans; Kidney Function Tests; Liver Transplantation; Male; Middle Aged; Peptide Fragments; Postoperative Complications; Renal Dialysis

Acute renal failure (ARF) is a serious complication following cardiac surgery. This first controlled study was undertaken to verify, if Urodilatin (URO) infusion can revert incipient oliguric ARF after cardiac surgery. We conducted a randomized, double blind trial comparing 7 URO (20 ng/kg/min) with 7 placebo patients. Inclusion criterion was oliguria/anuria (< 0.5 ml/kg/hour) refractory to conventional treatment including administration of dopamine and furosemide. No patient in the URO treated group, but 6 patients in the placebo group had to be hemofiltered or hemodialyzed (p < 0.005) during the 7 day treatment period. In the URO group all 7 patients demonstrated a rapid recovery of diuresis after 2 - 8 hours of treatment that persisted throughout the treatment period. In contrast, placebo treated patients remained oliguric. Serum creatinine (SC) decreased in URO treated patients. No adverse effects were observed during URO administration. After termination of URO, 2 patients underwent hemodialysis for elevated blood urea nitrogen (BUN) values. In the postoperative follow-up period of 60 days, 4 out of 7 placebo treated patients died while still on hemodialysis. In contrast, all URO patients survived. URO is an effective drug to reverse oliguric ARF following cardiac surgery. Prolonged renal failure and renal replacement therapy can be avoided.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Anuria; Atrial Natriuretic Factor; Cardiac Surgical Procedures; Diuretics; Dopamine; Double-Blind Method; Female; Furosemide; Humans; Male; Middle Aged; Oliguria; Patient Selection; Peptide Fragments; Postoperative Complications; Prospective Studies; Renal Dialysis

Acute renal failure is a serious problem following heart transplantation. In first uncontrolled clinical trials, Urodilatin revealed beneficial effects in the prophylaxis and therapy of acute renal failure following heart and liver transplantation. Here, we present the first randomized, placebo-controlled, double-blind study on 24 patients following heart transplantation to investigate whether prophylactic i.v. Urodilatin infusion can prevent acute renal failure requiring renal replacement therapy. Postoperative drug management was characterized by intravenous application of high furosemide, cyclosporine, and vancomycin doses. Urodilatin infusion was started postoperatively with a dose of 40 ng / kg bw / min for 6 days. 6 of the 12 patients in the Urodilatin group and 6 of the 12 patients in the placebo group had a stable diuresis (3 - 4 l / day) during the study period of 6 days. In contrast, the remaining 6 patients of each group developed oliguria / anuria and required subsequent hemofiltration / hemodialysis. Cumulative duration of hemofiltration (88 +/- 7.39 hours in the placebo treated patients versus 44 +/- 5.35 hours in the Urodilatin treated patients, p < 0. 05) as well as frequency of hemodialysis (3.0 +/- 0.49 times in the placebo group vs 1.2 +/- 0.29 times in the Urodilatin group, p < 0. 05) were significantly reduced using Urodilatin. Mean arterial blood pressure was stable during the Urodilatin infusion period and was not different to that observed in placebo patients. We conclude that Urodilatin does not reduce the incidence of acute renal failure and the subsequent requirement for hemofiltration / hemodialysis in our patient population, but seems to reduce the duration of hemofiltration and frequency of hemodialysis compared to the placebo group.

Topics: Acute Kidney Injury; Adolescent; Adult; Aged; Atrial Natriuretic Factor; Diuretics; Double-Blind Method; Heart Transplantation; Humans; Infusions, Intravenous; Middle Aged; Peptide Fragments

Renal failure after heart transplantation (HTx) still remains a serious problem, especially when cyclosporin A is used for immunosuppression in the early postoperative therapy. To preserve good renal function without reducing immunosuppressive cyclosporin A treatment, we administered urodilatin (CDD/ANP-95-126) in a long-term, low-dose infusion in addition to the usual medication after heart transplantation. From November 1990 to June 1991, 51 patients (46 male and 5 female; mean age 48 years) were treated with a 6-20 ng/kg bw.min infusion for 96 h after HTx. The renal function and hemodynamic parameters of these urodilatin-treated patients were compared in this sequential study with 40 patients (33 male and 7 female; mean age 49 years) who had undergone HTx previously from May to November, 1990, as controls. In this phase IIa study, both groups did not differ significantly with respect to age, sex, indication for HTx, and preoperative renal function. In comparison with controls patients treated with urodilatin had a significantly better renal function: a reduction in the peak plasma creatinine (PC values day 4: 1.5 +/- 0.11 vs. 2.19 +/- 0.19 mg/dl; P = 0.002), a lower peak serum urea (SU values day 4: 109 +/- 8 vs. 154.7 +/- 8.94 mg/dl; P = 0.0036), and a lower incidence of hemodialysis (6% vs. 10%) were observed. Adequate diuresis was maintained in spite of the reduction of furosemide by more than 60% (P = 0.005) on each day of urodilatin infusion in comparison with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Kidney Injury; Adult; Atrial Natriuretic Factor; Blood Pressure; Catecholamines; Cyclosporine; Diuretics; Female; Furosemide; Heart Rate; Heart Transplantation; Humans; Kidney Function Tests; Male; Middle Aged; Nitroglycerin; Peptide Fragments; Postoperative Care; Renal Dialysis

Raised cytokine levels and a hypoperfusion-associated decrease in glomerular filtration rate (GFR) are hallmarks of the genesis of septic acute renal failure (ARF). Therefore, anti-inflammatory as well as renal vasodilating therapeutic strategies may afford renal protection during septic ARF. The present study was designed to determine the effects of administration of urodilatin, pentoxifylline and theophylline to improve renal function in an ex-vivo model of 'septic renal injury'.. Eight series of experiments were performed: no intervention, perfusion with a suspension containing Escherichia coli bacteria (strain 536/21); E. coli + 10 microg/l urodilatin, E. coli + 20 microg/l urodilatin, E. coli + 100 microM theophylline, E. coli + 100 microM pentoxifylline and E. coli + URO 20 microg/l given 90 min after start of perfusion. Renal vascular and glomerular functional parameters as well as TNF-alpha release were analyzed up to 180 min.. Perfusion with E. coli caused an acute deterioration of renal vascular and glomerular function. URO 20 microg/l and PTX decreased renal vascular resistance (RVR) from 83.7 +/- 18.4 to 9.2 +/- 1.1 and 8.6 +/- 2.2 mm Hg/ml/min/g kidney and increased renal perfusion flow rate (PFR) from 8.2 +/- 1.5 to 14.6 +/- 0.8 and 14.1 +/- 2.2 ml/min/g kidney. As a result, GFR improved from 102.1 +/- 15.6 to 442 +/- 48.3 and 525.8 +/- 57 microl/min/g kidney during treatment with URO 20 microg/l and PTX, respectively. Renal TNF-alpha release was significantly reduced by URO 20 microg/l (from 178 +/- 23 to 45.2 +/- 2 and 47 +/- 3 pg/ml) in the E. coli + URO 20 microg/l and by PTX in the E. coli + PTX group if added to the perfusion medium upon start of perfusion. Interestingly, URO 20 microg/l also decreased RVR significantly from 62.2 +/- 6.1 to 35.9 +/- 6.0 mm Hg/ml/min/g kidney, improved PFR from 5.4 +/- 1.0 to 8.7 +/- 1.0 ml/min/g kidney, increased GFR from 160 +/- 43.3 to 280.7 +/- 27.9 microl/min/g kidney, and decreased TNF-alpha release to 122 +/- 18 pg/ml if applied 90 min after induction of septic ARF. In contrast, URO 10 microg/l did not significantly increase urine flow and did not appear to significantly improve renal perfusion. Theophylline showed no beneficial effects at all.. This suggests that urodilatin and pentoxifylline might be useful to protect renal function if given before a septic renal insult. Additionally, treatment with urodilatin is capable of restoring renal function in early Gram-negative sepsis-induced ARF even if given after the septic insult.

Topics: Acute Kidney Injury; Animals; Atrial Natriuretic Factor; Disease Models, Animal; Escherichia coli Infections; Humans; Kidney; Male; Pentoxifylline; Peptide Fragments; Perfusion; Rats; Rats, Sprague-Dawley

Topics: Acute Kidney Injury; Atrial Natriuretic Factor; Critical Care; Diuretics; Humans; Peptide Fragments

Topics: Acute Kidney Injury; Atrial Natriuretic Factor; Critical Care; Diuretics; Humans; Peptide Fragments

Acute renal failure (ARF) due to endotoxins is a common problem in clinical medicine. Endotoxins are released from the outer membrane of the gram-negative bacterial envelope and are composed of lipopolysaccharides (LPS). Although systemic hypotension often is present, LPS-induced ARF is characterized by marked intrarenal vasoconstriction. Both calcium channel blockers and natriuretic peptides are able to antagonize vasoconstricting signals and have been reported to exert beneficial effects in toxic and ischemic ARF: We investigated the effects of diltiazem (Dil, 300 micrograms/kg) or urodilatin (Uro, 40 micrograms/kg) or a combination of both (same doses) on renal function in early LPS-induced ARF: One hour after induction of ARF by i.v. injection of LPS glomerular filtration rate (GFR, clearance of fluorescence-marked inulin) was distinctly reduced to about 54% of basal values. In the following infusion period (60 min) a significant increase of GFR was observed with diltiazem (1.54 +/- 0.11 ml/min), urodilatin (1.60 +/- 0.10 ml/min) and the combination of both drugs (1.66 +/- 0.04 ml/min) compared to controls (1.17 +/- 0.08 ml/min). Combined administration did not cause additive effects. Also 60 and 120 minutes after stopping of drug infusion elevated GFR could be maintained in all experimental groups. Due to their vasorelaxing activity both Uro and Dil induced a decrease of mean arterial blood pressure in comparison with controls and revealed remarkable diuretic and natriuretic activity. In conclusion our results underline that marked intrarenal vasoconstriction in LPS-induced ARF can be antagonized by the well known relaxing potency of Uro and Dil towards vascular smooth muscle and mesangial cells. Both Uro and Dil were capable of improving suppressed renal function in the early phase of LPS-induced ARF in the rat as long as severe systemic hypotension is absent.

Topics: Acute Kidney Injury; Animals; Atrial Natriuretic Factor; Blood Pressure; Calcium Channel Blockers; Diltiazem; Diuretics; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Kidney; Lipopolysaccharides; Peptide Fragments; Rats; Rats, Sprague-Dawley; Sodium; Urodynamics

In humans as well as in experimental models the hallmark of ischemic acute renal failure (ARF) is a profound diminution in glomerular filtration rate (GFR) and renal blood flow. Both calcium antagonists and a-ANP have been reported to exert beneficial effects in ischemic ARF. No data, however, exist about combined administration of the natriuretic peptide urodilatin and calcium channel blockers. We therefore investigated the effects of urodilatin (URO, 40 micrograms/kg/h, i.v.) and diltiazem (DIL, 300 micrograms/kg/h, i.v.) in the rat given immediately after clamping of both renal arteries for 40 min. Compared to controls (0.07 +/- 0.01) depressed GFR (ml/min/100 g) was clearly elevated with URO (0.16 +/- 0.03), DIL (0.13 +/- 0.03) and URO + DIL (0.14 +/- 0.02) after the ischemic lesion. After cessation of drug delivery the beneficial effects were blunted in the URO group, in contrast to the DIL and URO + DIL group, where GFR was significantly elevated compared to controls even 3 h after starting reperfusion. Besides that also urine flow, sodium excretion and blood pressure were examined. In conclusion both URO and DIL exert beneficial effects in ischemic ARF in the rat while infused. In contrast to URO DIL showed prolonged beneficial effects even after cessation of drug delivery. An additional effect of both drugs could not be observed.

Topics: Acute Kidney Injury; Animals; Atrial Natriuretic Factor; Blood Pressure; Calcium Channel Blockers; Diltiazem; Disease Models, Animal; Diuretics; Drug Synergism; Female; Glomerular Filtration Rate; Kidney; Natriuresis; Peptide Fragments; Rats; Rats, Sprague-Dawley; Urodynamics

Acute renal failure was imminent in an 18-month-old male infant 20 days after unrelated BMT. The infant was treated with urodilatin (URO), a natriuretic vasorelaxant peptide. Diuresis increased 2 h after the commencement of URO infusion and the furosemide infusion was reduced from 5 mg/h to 2.5 mg/h. After seven days of URO treatment diuresis was normal, the serum creatinine level had decreased, and furosemide was reduced from 12 mg/kg bw/d to 1.8 mg/kg bw/d. No side effects were observed either during or following URO therapy. We consider URO to be a promising drug for the treatment, without any apparent side effects, of imminent or manifest acute renal failure in infants following BMT.

Topics: Acute Kidney Injury; Atrial Natriuretic Factor; Bone Marrow Transplantation; Cyclosporine; Diuretics; Humans; Infant; Male; Peptide Fragments

A pilot study was performed in patients after liver transplantation (Ltx) to examine the effect of continuous intravenous urodilatin (URO, CDD/ANP-95-126)-infusion as an alternative therapy of acute renal failure (ARF) resistant to conventional therapy. Eight patients who developed ARF after liver transplantation and fulfilled requirements for haemodialysis/haemofiltration were treated. After URO infusion was started, renal function improved and all patients developed a strong diuresis and natriuresis within 2-4 h. The extracellular expansion due to sodium and water retention in anuric/oliguric ARF lead to an increased central venous pressure (CVP) and elevated blood pressure. During the URO infusion CVP declined and systolic, as well as diastolic, blood pressure were stable. In six patients where haemodialysis/haemofiltration could be avoided, serum creatinine (SC) and blood urea nitrogen (BUN) declined during URO treatment and creatinine clearance (CC) also improved significantly. Fluid and electrolyte disturbances changed promptly and normalized. This was in concordance with renal excretion of electrolytes. Two patients still required haemodialysis/haemofiltration. The six patients who did not require haemodialysis/haemofiltration after URO treatment normalized concerning their renal function and did well in a control period of 12 weeks. The study shows that continuous low dose URO infusion may present a new concept for treatment of postoperative acute renal failure resistant to conventional therapy.

Topics: Acute Kidney Injury; Adult; Atrial Natriuretic Factor; Diuretics; Female; Hemodiafiltration; Humans; Liver Transplantation; Male; Middle Aged; Peptide Fragments; Pilot Projects

Beneficial effects of natriuretic peptides have been reported in different models of acute renal failure (ARF). Calcium antagonists can also improve renal function, especially in ischemic models of ARF. The aim of our study was to investigate the effects of urodilatin and diltiazem alone and in combination in uranyl nitrate-induced toxic ARF in the rat. Three hours after induction of ARF glomerular filtration rate (GFR) was clearly diminished to about 50% compared to basal values. Intravenous infusion of diltiazem and urodilatin revealed a significant increase of GFR that even continued after cessation of drug delivery. Combined administration of urodilatin and diltiazem had no additional effect, probably due to a more pronounced fall in blood pressure in this group. Besides their vasorelaxing and blood pressure lowering effects both drugs also revealed diuretic activity. In conclusion both urodilatin and diltiazem are able to elevate GFR in the early phase of toxic ARF in the rat.

Topics: Acute Kidney Injury; Amino Acid Sequence; Animals; Atrial Natriuretic Factor; Blood Pressure; Diltiazem; Diuretics; Female; Glomerular Filtration Rate; Kidney; Molecular Sequence Data; Peptide Fragments; Rats; Rats, Sprague-Dawley; Sodium; Uranyl Nitrate; Urodynamics

Topics: Acute Kidney Injury; Atrial Natriuretic Factor; Diuresis; Heart Transplantation; Humans; Liver Transplantation; Natriuresis; Peptide Fragments; Pilot Projects; Postoperative Complications

The present study was undertaken to: (a) clarify the comparative renal potency of bolus injection of the natriuretic peptides urodilatin and ANF99-126 in the rat; (b) establish whether or not intravenous (i.v.) infusion of urodilatin (200 ng/min) combined with dopamine (UD) to maintain mean arterial pressure could improve GFR or renal histology in established experimental ischemic acute renal failure (ARF) induced by 30 minutes of bilateral renal artery clamping; (c) assess comparative efficacies of nitroprusside, an activator of soluble guanylate cyclase, combined with dopamine (ND) or control infusions of dopamine alone (DA), under equivalent conditions; and (d) determine effects of intra-renal arterial infusions of the stable cGMP analogue dibutyryl-cGMP immediately after renal artery clamping (RAC). After initial dose finding studies, i.v. infusion of UD 24 hours after 30 minutes of RAC improved GFR over five hours from 0.24 +/- 0.04 to 1.0 +/- 0.16 ml/min in association with a threefold rise in plasma cGMP and a 13-fold increase in urinary cGMP excretion. Plasma creatinine dropped by 41% from 230 +/- 16 to 135 +/- 18 microM/liter and was still reduced 24 hours later with values averaging 106 +/- 14 compared to 274 +/- 53 microM/liter in non-treated animals. During infusion, UV and FENa+ increased from 1.4 +/- 0.2 to 8.3 ml/min, and from 2.9 +/- 0.5 to maximum values of 15.8 +/- 2.4%. ND or DA alone were less effective, increasing GFR only to 14 and 20%, respectively, of normal values, but improvements were not sustained; in contrast to UD, ND did not alter plasma or urinary cGMP. In addition, DBcGMP was ineffective in improving GFR during early ARF. Histologically UD, but not ND, markedly reduced the incidence of granular casts, tubular desquamation and tubular necrosis in cortical areas and increased the incidence of medullary mitoses.

Topics: Acute Kidney Injury; Animals; Atrial Natriuretic Factor; Creatinine; Dibutyryl Cyclic GMP; Diuresis; Dopamine; Drug Therapy, Combination; Glomerular Filtration Rate; Ischemia; Kidney; Natriuresis; Nitroprusside; Peptide Fragments; Rats; Rats, Sprague-Dawley