Loop diuretics in the management of acute renal failure: a prospective, double-blind, placebo-controlled, randomized study

Background: Studies on the role of loop diuretics in patients with acute renal failure (ARF) are largely retrospective, anecdotal, and poorly controlled. We report the results of a prospective, randomized, placebo-controlled, double-blind study examining the effect of loop diuretics on renal recovery, dialysis, and death in patients with ARF. Methods: Ninety-two patients with ARF were enrolled into the study. All received intravenous dopamine, 2 &mgr;g/kg body weight/min throughout, 20% mannitol, 100 ml every 6 h for the first 3 days, and, in a double-blind manner, either torasemide, frusemide, or placebo, 3 mg/kg body weight i.v. every 6 h for 21 days or until renal recovery or death. Results: Renal recovery, the need for dialysis, and death were not different in the three groups. Patients given a loop diuretic had a significant rise in urine flow rate in the first 24 h compared to placebo (P=0.02). Based on the urine flow rate during the first post-medication day patients were divided into two groups-oliguric (<50 ml/h) and non-oliguric (⩾50 ml/h). Non-oliguric patients had a significantly lower mortality than oliguric patients (43% vs 69%, P=0.01). However they were less ill (APACHE II score 17.2 vs 20.6, P=0.008) and had less severe renal failure at entry (creatinine clearance 14 ml/min vs 4 ml/min, P<0.0001). Conclusion: The use of loop diuretics in oliguric patients with ARF can result in a diuresis. There is no evidence that these drugs can alter outcome. Key words: acute renal failure; dopamine; loop diuretics; mannitol; oliguria; placebo-controlled trial; randomized      

Inhibition of COX-2 counteracts the effects of diuretics in rats.

BACKGROUND: It is well established that the diuretic- and renin-stimulated effects of loop diuretics can be attenuated by nonselective cyclooxygenase inhibitors. Since it is yet unclear which of the isoforms of cyclooxygenases, COX-1 and COX-2, is relevant in this context, our study aimed to determine the effects of selective COX-2 inhibition on the renal effects of the loop diuretic furosemide, as well as the diuretic hydrochlorothiazide, which acts on the distal tubule. METHOD: Male Sprague-Dawley rats were treated with furosemide (12 mg/day subcutaneously by osmotic pump) or hydrochlorothiazide (30 mg/kg body weight/day orally by gavage). In addition, parallel groups received rofecoxib (1 to 10 mg/kg body weight/day) for selective inhibition of COX-2. Controls were treated with vehicle. RESULTS: Induction of COX-2 mRNA expression due to furosemide was paralleled by increased renal excretion of prostanoids. Also, hydrochlorothiazide led to a rise in prostanoid excretion. Rofecoxib blunted the diuretic-induced increase in prostanoid excretion, thus confirming an effective blockade of COX-2. Moreover, the COX-2 inhibitor rofecoxib dose-dependently attenuated diuresis and saluresis, as well as the stimulation of the renin system induced by furosemide. Furthermore, rofecoxib completely reversed diuresis and saluresis and prevented the increase of plasma renin activity induced by hydrochlorothiazide. CONCLUSIONS: These findings suggest that COX-2-derived prostanoids are of major relevance in modulating the renal effects of diuretics. COX-2 inhibitors might be valuable drugs to treat salt and water wasting during Bartter and Gitelman diseases.     

Intraplatelet calcium levels in patients with acute renal failure before and after the administration of loop diuretics.

BACKGROUND: Intracellular calcium [Ca](i) has been found to be elevated in hypoxic cells in vitro and in erythrocytes and lymphocytes from patients who are septic. Loop diuretics decrease [Ca](i) in platelets from patients with hypertension and in red blood cells from normal volunteers. We report the results of a study designed to measure [Ca](i) in platelets from patients with acute renal failure (ARF) before and after the administration of loop diuretics. METHODS: Sixteen healthy adults and seven patients with ARF were enrolled into the study. Intraplatelet calcium was measured using a fluorescent probe (quin2). Patients with ARF all received intravenous (i.v.) dopamine, 2 microg/kg body weight, and 20% mannitol, 100 ml every 6 h and, in double-blind manner, either torasemide, frusemide, or placebo, 3 mg/kg body weight i.v. every 6 h. Data from subjects given either frusemide or torasemide have been considered together and termed the diuretic group. RESULTS: Basal levels of [Ca](i) in platelets from patients with ARF were significantly higher than in controls (126.9 +/-3 5.7 nmol/l vs 85.7 +/- 22.2 nmol/l, P = 0.02), but were not affected by the administration of loop diuretic (126.9 +/- 35.7 nmol/l vs 165.9 +/- 49.7 nmol/l, P = 0.09, pre- vs post-diuretic). CONCLUSIONS: Intraplatelet calcium is raised in patients with ARF. Loop diuretics have no significant effect on intraplatelet calcium in these patients.     

Acute renal failure after the use of angiotensin-converting-enzyme inhibitors in patients without renal artery stenosis.

During a 4-year period, acute renal failure was observed in 27 patients (mean age 65 years) treated by various angiotensin-converting-enzyme (ACE) inhibitors for hypertension, heart failure, or a combination of both. None had significant renal artery stenosis on angiography. Overt volume depletion was present in 21 and hypotension in 12 cases. All patients received diuretic therapy and/or a low-salt diet. Other facilitating factors included cardiac failure, pre-existing chronic renal insufficiency, combined therapy with non-steroidal anti-inflammatory drugs, and diabetes mellitus. Twenty-two patients had two or more of these factors at presentation. A renal biopsy performed in 10 cases showed severe arteriosclerosis of small renal arteries in eight and acute tubular necrosis in five instances. Therapy comprised volume expansion, and withdrawal of diuretics and, except in two patients, of ACE inhibitors. Twenty-one patients recovered normal renal function, two died, and permanent renal damage remained in four. These results suggest that sodium depletion has a critical role in inducing acute renal failure, whose outcome is not always benign. A combination of diuretics and ACE inhibitors should be prescribed with caution, especially in older patients with small as well as with large renal vessel disease.     

Significance of the fractional excretion of urea in the differential diagnosis of acute renal failure

BACKGROUND: Fractional excretion of sodium (FENa) has been used in the diagnosis of acute renal failure (ARF) to distinguish between the two main causes of ARF, prerenal state and acute tubular necrosis (ATN). However, many patients with prerenal disorders receive diuretics, which decrease sodium reabsorption and thus increase FENa. In contrast, the fractional excretion of urea nitrogen (FEUN) is primarily dependent on passive forces and is therefore less influenced by diuretic therapy. METHODS: To test the hypothesis that FEUN might be more useful in evaluating ARF, we prospectively compared FEUN with FENa during 102 episodes of ARF due to either prerenal azotemia or ATN. RESULTS: Patients were divided into three groups: those with prerenal azotemia (N = 50), those with prerenal azotemia treated with diuretics (N = 27), and those with ATN (N = 25). FENa was low only in the patients with untreated plain prerenal azotemia while it was high in both the prerenal with diuretics and the ATN groups. FEUN was essentially identical in the two pre-renal groups (27.9 +/- 2.4% vs. 24.5 +/- 2.3%), and very different from the FEUN found in ATN (58.6 +/- 3.6%, P < 0.0001). While 92% of the patients with prerenal azotemia had a FENa <1%, only 48% of those patients with prerenal and diuretic therapy had such a low FENa. By contrast 89% of this latter group had a FEUN <35%. CONCLUSIONS: Low FEUN (相似文献   

Torsemide versus furosemide after continuous renal replacement therapy due to acute renal failure in cardiac surgery patients

Diuretic therapy in ARF (acute renal failure) is mainly done with loop diuretics, first of all furosemide. Torsemide has a longer duration of action and does not accumulate in renal failure. In chronic and acute renal failure, both diuretics have been effectively applied, with a more pronounced diuretic effect for torsemide. In this study, the effects of torsemide versus furosemide on renal function in cardiac surgery patients recovering from ARF after continuous renal replacement therapy (CRRT) were studied. Twenty-nine critically ill patients admitted to an intensive care unit at a university teaching hospital after cardiac surgery recovering from ARF after CRRT were included in this prospective, controlled, single-center, open-labeled, randomized clinical trial. Inclusion criteria were urine output >0.5 mL/kg/h over 6 h under CRRT. Torsemide and furosemide dosages were adjusted with the target urine output being 0.8-1.5 mL/kg/h. Hemodynamic data, urine output, volume balance, serum creatinine clearance, electrolytes, blood urea nitrogen, serum creatinine, renin, and aldosterone concentrations were measured. Fourteen patients were included in the furosemide group and 15 patients in the torsemide group. Dosages of 29 (0-160) mg torsemide and a dosage of 60 (0-240) mg furosemide were given every 6 h in each group, respectively. The dosage given at the end of the study decreased significantly in furosemide and torsemide treated patients. Urine output, 24 h balance, and serum creatinine clearance did not differ significantly between groups. Urine output decreased in both groups, mostly dose-dependent in the torsemide group. The intragroup comparison of the first time-interval after inclusion with the last time-interval showed a significant increase in serum creatinine and blood urea nitrogen in the furosemide group. Renin and aldosterone concentrations did not show significant differences. In conclusion, torsemide and furosemide were effective in increasing urine output. Torsemide might show a better dose-dependent diuretic effect in ARF patients after CRRT treatment. Serum creatinine and blood urea nitrogen elimination were less pronounced in the furosemide group.     

肝移植术后早期急性肾功能衰竭5例临床分析

目的总结肝移植术后早期急性肾功能衰竭的防治经验。方法回顾性分析5例肝移植受者术后早期发生急性肾功能衰竭临床资料,手术方式为改良背驮式肝移植术,其中4例术前即合并肾功能不全。结果5例术后早期急性肾功能衰竭患者3例通过调整免疫抑制方案和改善肾脏灌注及利尿治疗肾功能恢复;2例给予连续性肾脏替代治疗后肾功能恢复。结论肝移植术后免疫抑制剂的个体化应用,积极改善肾脏灌注,必要时选择血液透析治疗,有助于防治肝移植术后早期急性肾功能衰竭。     

Diuretics versus angiotensin-converting enzyme inhibitors in autosomal dominant polycystic kidney disease

Hypertension, which occurs commonly and early in autosomal dominant polycystic kidney disease (ADPKD), affects both renal and patient outcome. However, there is no consensus about the type of antihypertensive therapy that is most appropriate for patients with ADPKD. This historical prospective, nonrandomized study was designed to investigate the effect on renal function of diuretics versus angiotensin-converting enzyme (ACE) inhibitors in hypertensive patients with ADPKD who entered the study with comparable renal function. Among hypertensive ADPKD patients followed in our center, patients taking diuretics without any ACE inhibitors were included in the diuretic group (n = 14, male/female ratio 5/9, mean age 47 years), whereas patients taking ACE inhibitors but no diuretics were included in the ACE inhibitor (ACEI) group (n = 19, male/female ratio 11/8, mean age 41 years). For comparable blood pressure control, 21% of the ACEI group and 64% of the diuretic group (p < 0.05) needed additional antihypertensive medications. After an average follow-up period of 5.2 years, the creatinine clearance decreased significantly in the diuretic group (74 vs. 46 ml/min/1.73 m2, p < 0.0001) and in the ACEI group (83 vs. 71 ml/min/1.73 m2, p = 0.0005). The decrement in creatinine clearance was significantly larger in the diuretic group than the ACEI group (p < 0.05). The annual decrease in creatinine clearance was 5.3 ml/min/1.73 m2 in the diuretic group and 2.7 ml/min/1.73 m2 in the ACEI group (p < 0.05). A significant increase in urinary protein excretion occurred in the diuretic but not in the ACEI group. Hypertensive ADPKD patients treated with diuretics had a faster loss of renal function as compared with patients treated with ACE inhibitors, despite similar blood pressure control. This result will need to be further examined in a randomized study.     

Should we use diuretics in acute renal failure?

Because oliguria is a bad prognostic sign in patients with acute renal failure (ARF), diuretics are often used to increase urine output in patients with or at risk of ARF. From a pathophysiological point of view there are several reasons to expect that loop diuretics also could have a beneficial effect on renal function. However, clinical trials on the prophylactic use of loop diuretics rather point to a deleterious effect on parameters of kidney function. In patients with established ARF loop diuretics have been shown to increase urine output, which may facilitate patient management. A beneficial effect on renal function has, however, not been demonstrated. On the other hand, such an effect cannot be excluded because the available trials lack statistical power. Possible explanations for the absence of a renoprotective effect are discussed. The evidence for a renoprotective effect of mannitol is restricted to the setting of renal transplantation.     

Akutes Nierenversagen und Sepsis

Acute renal failure (ARF) is clinically defined as an abrupt, but in principle reversible deterioration of glomerular and tubular function. Regarding pathophysiology, ARF is caused by ischemic renal conditions and toxic mediators. Sepsis is the most common cause of ARF in the intensive care unit and ARF is an independent risk factor for lethality of septic patients. Interventions to protect the kidneys against ARF include preliminary optimization of renal perfusion by volume load with cristalloid solutions and the administration of vasopressors. Daily maximum permissible dosages for colloids should not be exceeded and hyperoncotic colloid solutions should be generally avoided. Dopamine in “renal dosage” is nowadays obsolete. Loop diuretics produce diuresis and can be beneficial to extrarenal organs by improving fluid homeostasis, however diuretics do not improve kidney function and outcome. Therefore, diuretics are not indicated for patients with imminent or existing ARF. Septic patients with ARF can be treated by intermittent and continuous forms of renal replacement therapy, whereas continuous convective and intermittent diffusive methods are equivalent when utilizing an ultrafiltration rate ≥20 ml/h?kg body weight or a therapeutic interval ≥3 times/week.     

Nephrotoxicity with cyclooxygenase 2 inhibitor use in children

The nephrotoxic potential of anti-inflammatory drugs alone and in compound preparations has been known for over fifty years. Nephrotoxicity associated with selective cyclooxygenase 2 (COX-2) inhibitor use is reported in adult patients but not in children. We present here the first report of reversible acute renal failure associated with the COX-2 inhibitor rofecoxib (Vioxx) in three children. Patient 1, an 18 month old girl with neonatal Bartter syndrome, developed acute renal failure with a peak creatinine of 1.9 mg/dl (164 μmol/l) and severe hyperkalemic metabolic acidosis. Patient 2, a 14 year old boy with a history of rheumatic fever, developed acute renal failure with a peak creatinine of 2.7 mg/dl (240 μmol/l). While patient 3, a healthy 14 year old girl, developed acute renal failure and tubulointerstitial nephritis confirmed on renal biopsy with a peak creatinine of 3.3 mg/dl (287 μmol/L). All children had been taking non-selective non-steroidal anti-inflammatory drugs (NSAID’s) immediately prior to rofecoxib use. Renal function returned to normal within one week in all three patients and has remained normal at follow-up. This paper highlights the nephrotoxic risk of COX-2 inhibitor use in the pediatric population.     

Interaction of cyclosporine and FK506 with diuretics in transplant patients

BACKGROUND: The calcineurin inhibitors cyclosporine and FK506 are widely used for immunosuppression in solid organ transplantation. One of the side effects of these agents is renal magnesium wasting. The site of action and molecular mechanism of this effect are not known. We hypothesized that agents such as diuretics that cause renal magnesium wasting through a similar action would not have an additive effect on magnesium deficiency with calcineurin inhibitors. METHODS: The records of 50 heart transplant patients on calcineurin inhibitors were reviewed to determine levels of serum magnesium and required replacement dose of magnesium, diuretic usage, and other laboratory values. RESULTS: Loop diuretics did not change either the magnesium level or magnesium replacement requirements in patients on calcineurin inhibitors. In contrast, the thiazide diuretic resulted in an increase in serum magnesium and a decrease in magnesium replacement. Results were similar when the cyclosporine or FK506 groups were evaluated alone. Patients taking FK506 had lower serum magnesium values and higher requirements for magnesium replacement compared with patients taking cyclosporine. CONCLUSION: We conclude that calcineurin inhibitors and loop diuretics have a similar site of action.     

Acute tubular necrosis due to captopril

Angiotensin-converting enzyme (ACE) inhibitors are standard therapy for congestive cardiac failure. ACE inhibitors have been used worldwide and are usually safe and have relatively few side effects. Hypotension can develop with the first dose of captopril and can lead to symptomatic renal hypoperfusion with subsequent acute renal failure (ARF). The case of a 65-year-old patient with congestive heart failure who developed acute renal failure following the first dose of captopril is described. He required hemodialysis for 8 weeks for the improvement of his renal function and urinary output. The renal biopsy confirmed the presence of acute tubular necrosis. The reversibility of captopril-induced ARF is confirmed and the patient made an uneventful recovery. An immunoallergic mechanism is not thought to have been responsible for this adverse effect. It is advised that caution should be exerted in giving ACE inhibitors to elderly patients with congestive heart failure, particularly if they are on diuretics. Routine biochemical monitoring is suggested before and during captopril therapy.     

Acute renal dysfunction associated with selective COX-2 inhibitor therapy

The recent release of the selective cyclooxygenase-2 (COX-2) enzyme inhibitors for the treatment of various inflammatory disorders and pain syndromes has been associated with a clear-cut decrease in adverse gastrointestinal effects. The nephrotoxic effect of selective COX-2 inhibitors has not yet been firmly established. We report a case of reversible acute renal failure due to rofecoxib treatment in an elderly patient with several risk factors associated with traditional nonselective nonsteroidal anti-inflammatory drug (NSAID)-related nephrotoxicity. It is prudent to approach therapy with selective COX-2 inhibitors cautiously and in a fashion similar to traditional NSAID therapy for patients with risk factors that induce prostaglandin-dependent renal function.     

Renal failure after anti-D globulin treatment of idiopathic thrombocytopenic purpura

Idiopathic thrombocytopenic purpura (ITP) is a disorder of rapid destruction of antibody-coated platelets. Anti-D immune globulin has been used for treatment of ITP in the United States since 1995. Initial studies identified no significant side effects of treatment. However, a recent report highlighted occasional episodes of intravascular hemolysis after anti-D immune globulin. We describe two children with ITP who developed acute renal failure (ARF) after treatment with anti-D immune globulin and also analyze ten additional cases of ARF reported to the manufacturer, Cangene Corporation, through postmarketing surveillance. All episodes of ARF were associated with intravascular hemolysis. Four patients required dialysis. Patient age ranged from 1 to 82 years, but those requiring dialysis were all under age 15 years. Several patients with ARF had preexisting creatinine elevation. Three of the patients with ARF had serologic evidence of acute Epstein-Barr virus (EBV) infection. Renal biopsy in one patient showed acute tubular necrosis, with findings consistent with pigment nephropathy. Anti-D immune globulin, used to treat ITP, may be associated with intravascular hemolysis and resultant ARF. Renal function should be monitored in patients with evidence of intravascular hemolysis. Children and adolescents may have increased risk of ARF requiring dialysis. Received: 30 March 2001 / Revised: 17 September 2001 / Accepted: 18 September 2001     

Hypertensive crisis after discontinuation of an angiotensin-converting enzyme inhibitor in a patient with renal dysfunction

SUMMARY: A 54-year-old woman with hypertension treated for 2 years with enalapril, 10 mg daily, was admitted to hospital because of progressively worsening renal function. There was no evidence of scleroderma, except for the presence of anticentromere antibodies. to prevent hyperkalaemia and further deterioration of renal function, enalapril was abruptly withdrawn and replaced with a calcium antagonist on the second hospital day, but hypertensive crisis developed. Renal failure requiring haemodialysis developed 2 weeks after admission. Findings of a renal biopsy were consistent with scleroderma kidney. Scleroderma is difficult to diagnose in the absence of cutaneous symptoms. Therefore, angiotensin-converting enzyme inhibitors should only be discontinued with care in patients with renal dysfunction if there is the possibility of scleroderma without skin changes.     

COX-2 inhibitor induced anuric renal failure in a previously healthy young woman

Side effects of nonsteroidal anti-inflammatory drugs (NSAIDs) most commonly affect the gastrointestinal tract and the kidney. The recent release of selective cyclooxygenase-2 (COX-2) inhibitors has been associated with a decrease in adverse gastrointestinal effects. However, the nephrotoxic potential of these drugs still remains controversial. Here, we report the case of a previously healthy woman with reversible acute renal failure associated with eight days of anuria following the administration of valdecoxib, a newly released selective cyclooxygenase-2 inhibitor, during an episode of acute febrile pyelonephritis. We suggest that selective COX-2 inhibitors should not be used in patients with volume contraction and underlying renal disease.     

COX-2 inhibitors and acute interstitial nephritis: case report and review of the literature

We report a case of biopsy-proven acute interstitial nephritis (AIN) in a 50-year-old diabetic woman, who had been treated with celecoxib for 4 weeks before presentation. She presented with clinical findings of renal proximal tubulopathy, aseptic leukocyturia and acute renal failure. A kidney biopsy specimen showed AIN with intense tubuli and eosinophilic infiltrate in the interstitium. She recovered normal renal function two weeks after cessation of celecoxib and use of a corticosteroid. A review of the literature yielded eight cases of COX-2 inhibitor-associated AIN with a biopsy-proven diagnosis. Among the reported cases, AIN was diagnosed after an average of 8.3 months of therapy (SD 12 months, range 3 days - 3 years) with 25 mg rofecoxib or 200 mg celecoxib daily. Common symptoms included asthenia, anorexia, nausea and vomiting. The classic triad of fever, rash and eosinophilia was uncommon. Typical laboratory features included hematuria, proteinuria, eosinophilia. Renal failure was common at the time of diagnosis. Mean serum creatinine levels were 0.86 +/- 0.11 mg/dl, 5.66 +/- 3.50 mg/dl and 1.15 +/- 0.24 before treatment, at time of diagnosis and 1 - 2 months after COX-2 inhibitor withdrawal, respectively. Three patients required emergency hemodialysis. After cessation of COX-2 inhibitor treatment, patients recovered completely with a normalized serum creatinine level after one to two months. Management consisted of withdrawal of the COX-2 inhibitor drug and in four patients, corticosteroid therapy was well-tolerated and may have been beneficial.     

Tolvaptan alleviates excessive fluid retention of nephrotic diabetic renal failure unresponsive to furosemide

Patients with diabetic nephropathy develop nephrotic syndrome and may show limited response to conventional therapy. They often require earlier initiation of renal replacement therapy because they become refractory to diuretics, and experience excessive fluid retention. We aimed to investigate the efficacy of tolvaptan, an oral arginine vasopressin type 2 receptor antagonist, in a case series of 14 severe diabetic renal failure patients who were severely refractory to maximal doses of furosemide and had excessive fluid retention despite preserved cardiac function and residual renal function. All 14 patients experienced immediate and sustained water diuretic effects, resulting in alleviation of congestive heart failure. None required initiation of renal replacement therapy. Tolvaptan promptly increased urine volume and free water clearance, reversed progressive fluid retention, and alleviated congestive heart failure. Thus, tolvaptan could serve as a potential adjunct therapy for severe diabetic renal failure patients with excessive fluid retention and congestive heart failure.     

Continuous low-dose human atrial natriuretic peptide promotes diuresis in oliguric patients after living donor liver transplantation

Human atrial natriuretic peptide (ANP) is beneficial for the prophylaxis of acute renal failure (ARF) after liver transplantation (OLT). We evaluated renal function in OLT patients with or without ARF, describing cases unresponsive to loop diuretics successfully treated with continuous low-dose ANP infusion without hemodialysis. Twenty-seven consecutive adult-to-adult living donor liver transplantations (LDLTs) were performed in 26 patients. One case was excluded due to the need for continuous hemodialysis (HD) during the operation. Of the 26 cases, 6 (23%, group 2) developed ARF in the first 30 days after LDLT; the other 20 were ARF-free (group 1). The median follow-up was 24 months. No patient required either continuous or intermittent HD. Only one patient died due to multiple liver abscesses. Mean preoperative serum creatinine (sCr) value and intraoperative blood loss in group 2 were significantly higher than those in group 1. Three cases in group 2 failed to improve on high-dose loop diuretics with low-dose dopamine, exhibiting fluid overload. The remaining three cases in group 2 responded to conventional diuretic treatments. Continuous low-dose ANP was started 2, 4, or 5 days after LDLT, and urine output significantly increased after ANP administration. The serum creatinine values were 1.1, 1.2, and 1.1 at 1 month and 1.0, 0.9, and 0.6 mg/dL at 6 months after LDLT. Massive blood loss during the operation caused ARF, but did not affect renal function after LDLT. Continuous low-dose ANP improved renal function and diuresis for oliguric ARF patients, preventing the need for HD or continuous venovenous hemodialysis.