Acute Kidney Injury Resulting From Hemoglobinuria After Pulsed-Field Ablation in Atrial Fibrillation: Is it Preventable?

BACKGROUND: High-voltage pulses can cause hemolysis. OBJECTIVES: The authors evaluated the occurrence of hemoglobinuria after pulsed-field ablation (PFA) and its impact on renal function in patients with atrial fibrillation (AF). METHODS: A consecutive series of patients with AF undergoing PFA were included in this analysis. The initial patients who did not receive postablation hydration immediately after the procedure were classified as group 1 (n = 28), and the rest of the study patients who received planned fluid infusion (0.9% sodium chloride ≥2 L) after the procedure were categorized as group 2 (n = 75). RESULTS: Of the 28 patients in group 1, 21 (75%) experienced hemoglobinuria during the 24 hours after catheter ablation. The mean postablation serum creatinine (S-Cr) was significantly higher than the baseline value in those 21 patients (1.46 ± 0.28 mg/dL vs 0.86 ± 0.24 mg/dL, P < 0.001). Of those 21 patients, 4 (19%) had S-Cr. >2.5 mg/dL (mean: 2.95 ± 0.21 mg/dL). The mean number of PF applications was significantly higher in those 4 patients than in the other 17 patients experiencing hemoglobinuria (94.63 ± 3.20 vs 46.75 ± 9.10, P < 0.001). In group 2 patients, no significant changes in S-Cr were noted. The group 2 patients received significantly higher amounts of fluid infusion after catheter ablation than did those in group 1 (2,082.50 ± 258.08 mL vs 494.01 ± 71.65 mL, P < 0.001). In multivariable analysis, both hydration (R2 = 0.63, P < 0.01) and number of PFA applications (R2 = 0.33, P < 0.01) were independent predictors of postprocedure acute kidney injury. CONCLUSIONS: On the basis of our findings, both the number of PFA applications and postablation hydration were independent predictors of renal insult that could be prevented using planned fluid infusion immediately after the procedure.

Balloon-occluded retrograde transvenous obliteration of gastric varices: use of CT-guided foam sclerotherapy to optimize technique.

OBJECTIVE: Balloon-occluded retrograde transvenous obliteration has been traditionally based on liquid sclerotherapy. However, overdose and systemic spillage of liquid sclerosant can cause severe complications, such as hemolysis, which lead to hemoglobinuria, allergy, acute respiratory distress syndrome, and other disorders. The purpose of this study was to evaluate the performance of foam sclerotherapy with C-arm CT guidance to reduce the amount of sclerosant and to optimize the safety of balloon-occluded retrograde transvenous obliteration while preserving its efficacy. MATERIALS AND METHODS: Twenty consecutively registered patients with gastric varices underwent balloon-occluded retrograde transvenous obliteration with polidocanol foam. C-arm CT guidance was used to confirm gas filling of the target vessels. In this retrospective analysis of a prospectively encoded database, total net doses of polidocanol used for transvenous obliteration and of contrast medium used for venography before transvenous obliteration were compared, and subsequent complications, including hemoglobinuria, were documented. RESULTS: In all patients, foam was observed in the target vessels at C-arm CT. The mean dose of polidocanol used for balloon-occluded retrograde transvenous obliteration (3.9 ± 1.5 mL) was significantly smaller (p < 0.001) than the dose of contrast medium used for venography (16.4 ± 7.9 mL). Hemoglobinuria was found in only one patient. Except in one instance of recanalization, full variceal thrombosis was confirmed at contrast-enhanced CT 1 week after transvenous obliteration (success rate, 95%). In one patient, air migrated into the liver during transvenous obliteration but was spontaneously absorbed. No serious complication occurred. CONCLUSION: Balloon-occluded retrograde transvenous obliteration with polidocanol foam under C-arm CT guidance allowed significant reduction of sclerosant dose and resulted in a low complication rate while a high technical success rate and efficacy were maintained.

Pathobiology and diagnosis of clostridial hepatitis in animals.

Clostridia can cause hepatic damage in domestic livestock, and wild and laboratory animals. Clostridium novyi type B causes infectious necrotic hepatitis (INH) in sheep and less frequently in other species. Spores of C. novyi type B can be present in soil; after ingestion, they reach the liver via portal circulation where they persist in phagocytic cells. Following liver damage, frequently caused by migrating parasites, local anaerobic conditions allow germination of the clostridial spores and production of toxins. C. novyi type B alpha toxin causes necrotizing hepatitis and extensive edema, congestion, and hemorrhage in multiple organs. Clostridium haemolyticum causes bacillary hemoglobinuria (BH) in cattle, sheep, and rarely, horses. Beta toxin is the main virulence factor of C. haemolyticum, causing hepatic necrosis and hemolysis. Clostridium piliforme, the causal agent of Tyzzer disease (TD), is the only gram-negative and obligate intracellular pathogenic clostridia. TD occurs in multiple species, but it is more frequent in foals, lagomorphs, and laboratory animals. The mode of transmission is fecal-oral, with ingestion of spores from a fecal-contaminated environment. In affected animals, C. piliforme proliferates in the intestinal mucosa, resulting in necrosis, and then disseminates to the liver and other organs. Virulence factors for this microorganism have not been identified, to date. Given the peracute or acute nature of clostridial hepatitis in animals, treatment is rarely effective. However, INH and BH can be prevented, and should be controlled by vaccination and control of liver flukes. To date, no vaccine is available to prevent TD.

Acute post-parturient haemoglobinuria in dairy cows and phosphorus status.

During the conduct of an experiment designed to examine the nutritional management of dairy cows in late pregnancy, four cows out of 72 suffered from acute haemoglobinuria two to four weeks after calving. Thirty-six thin and 36 fat cows were individually fed one of three diets based on a total mixed ration with different energy or protein concentrations during the last 3 to 4 weeks before expected calving date. After calving, cows grazed pasture and were offered 6 kg dry matter of pelleted concentrates daily. The P concentrations of the feeds offered suggested that the cows' diets were marginally deficient in P relative to requirements. Plasma P concentrations were significantly (P < 0.05) lower in fat cows than in thin cows during the first 6 weeks of lactation (0.87 versus 1.12 mmol/L), but precalving diet had no effect (P > 0.05). Concentrations of plasma inorganic P of the four fat cows that developed acute haemoglobinuria were less than 0.3 mmol/L. However, plasma P concentrations in another 12 cows, none of which displayed overt symptoms, declined to similar levels. It appeared that inadequate dietary P may have predisposed cows to acute haemoglobinuria, but the precipitating cause was not readily obvious.

Congenital CD59 Deficiency.

The severe clinical symptoms of inherited CD59 deficiency confirm the importance of CD59 as essential complement regulatory protein for protection of cells against complement attack, in particular protection of hematopoietic cells and human neuronal tissue. Targeted complement inhibition might become a treatment option as suggested by a case report. The easy diagnostic approach by flow cytometry and the advent of a new treatment option should increase the awareness of this rare differential diagnosis and lead to further studies on their pathophysiology.

Swine as a model for cardiovascular research: improved cardiopulmonary bypass techniques.

A large-animal model is essential for the assessment of functional parameters in cardiovascular surgical research. To date the canine model has been used successfully because of its availability and tolerance to cardiopulmonary bypass. However, because of decreased availability and increased cost, an alternative animal model is now needed. The swine model has been used in experimental cardiac procedures, but complications during cardiopulmonary bypass have presented a formidable challenge. These complications include enormous fluid shifts from the vascular bed, increased metabolic acidosis, and marked hemoglobinuria. To eliminate these deleterious complications within the swine model, a number of technical alterations were achieved. The priming solution used for the extracorporeal circuit was altered to consist of 1000 mL lactated Ringer's solution. 500 mL 20% mannitol, 500 mL 6% dextran in 5% detrose solution. 50 mEq sodium bicarbonate, and 10,000 IU heparin. The extracorporeal circuit employed the use of membrane oxygenation. Three different blood flow rates (150, 175, and 200 mL/kg min-1) were studied. We conclude that the optimum blood flow rate for cardiopulmonary bypass in swine is in the range of 175-200 mL/kg min-1. Membrane oxygenation results in less damage to blood during cardiopulmonary bypass. The asanguinous hyperosmolar priming solution is beneficial for cardiopulmonary bypass in swine to greatly reduce fluid shifts, prevent metabolic acidosis, and eliminate hemoglobinuria.

The design and application of a pediatric centrifugal pump.

This centrifugal pump (CP) includes two parts: the blood pump and the driving apparatus. They are connected by six twin magnetic disc plates and driven by a magnetic DC motor (120W). The blood pump had six leaves deadlocked between two plastic discs. Six leaves were set at 30 degrees angles, separately. In the lower chamber of the CP, there was an inlay magnetic disc, which is connected with the disc leaves by an axis. This axis was sealed by silicon rubber and a ceramic ring. The priming volume of the blood chamber was 34 ml. In vitro testing showed that the free hemoglobin caused by the CP was much less than that caused by a roller pump after 180 min. The effect of this CP on blood cell damage was also studied in an animal model. Six goats were placed on cardiopulmonary bypass for 180 min. Perfusion flow rates were maintained between 1.5 and 2.5 L/min. The plasma free hemoglobin was lower in the CP group (6.04 mg/dL) than in the roller pump group (32.25 mg/dL), p < 0.01. The CP has been used in ten pediatric patients undergoing cardiopulmonary bypass surgery. The patients' ages were from three to five years, and body weights were from 15 to 20 kg. Perfusion flow rates were maintained between 1.8 and 2.5 L/min, and bypass times were from 30 to 50 min. The rotation speeds were from 2000 to 2500 rpm. All the patients recovered smoothly, and no hemoglobinuria occurred.

Phitsanulok population: the highest incidence of hemoglobin E in the northern provinces of Thailand and PND counseling.

Phitsanulok is a province situated in the southern part of northern Thailand. Studies of hemoglobinopathies of 2,806 individuals during the period 1988-1990 showed an overall incidence of hemoglobinopathies of 38.89%, with HbE as high as 25% which is the highest incidence of HbE in the North of Thailand. Buddhachinaraj Hospital conducted a maternal screening study on 1,015 pregnant women in 1991 as part of a prevention/control program and found that 22.56% (229 women) had hemoglobinopathies. Of those, 102 (44.54%) individuals (83.33% HbE heterozygotes and 8.82% HbE homozygotes) with their spouses participated in a prenatal diagnosis (PND) counseling program; 100% of the females and 96% of the male were willing to accept PND; 71% of the females and 75.6% of the males had no moral objection in PND.

Cardiopulmonary bypass-associated acute kidney injury: a pigment nephropathy?

Acute kidney injury (AKI) is a common and serious postoperative complication following exposure to cardiopulmonary bypass (CPB). Several mechanisms have been proposed by which the kidney can be damaged and interventional studies addressing known targets of renal injury have been undertaken in an attempt to prevent or attenuate CPB-associated AKI. However, no definitive strategy appears to protect a broad heterogeneous population of cardiac surgery patients from CPB-associated AKI. Although the association between hemoglobinuria and the development of AKI was recognized many years ago, this idea has not been sufficiently acknowledged in past and current clinical research in the context of cardiac surgery-related AKI. Hemoglobin-induced renal injury may be a major contributor to CPB-associated AKI. Accordingly, we now describe in detail the mechanisms by which hemoglobinuria may induce renal injury and raise the question as to whether CPB-associated AKI may actually be, in a significant part, a form of pigment nephropathy where hemoglobin is the pigment responsible for renal injury. If CPB-associated AKI is a pigment nephropathy, alkalinization of urine with sodium bicarbonate might protect from: (1) tubular cast formation from met-hemoglobin; (2) proximal tubular cell necrosis by reduced endocytotic hemoglobin uptake, and (3) free iron-mediated radical oxygen species production and related injury. Sodium bicarbonate is safe, simple to administer and inexpensive. If part of AKI after CPB is truly secondary to hemoglobin-induced pigment nephropathy, prophylactic sodium bicarbonate infusion might help attenuate it. A trial of such treatment might be a reasonable future investigation in higher risk patients receiving CPB.

Conservative treatment of hemolytic complication following coil embolization in two adult cases of patent ductus arteriosus.

Two adult cases of relatively large patent ductus arteriosus (PDA) were treated by coil embolization, but were complicated by hemolysis that was successfully managed by medical treatment. Case 1 was a 67-year-old woman and Case 2 was a 71-year-old woman with a PDA of minimal diameter of 5.3 mm and 5.5 mm, respectively. The approach was via the pulmonary artery and 2 coils were delivered simultaneously into the ductus, known as the 'kissing coil technique'. Although immediately after the procedure only a small residual shunt was revealed by aortogram, hemolysis occurred for several hours after the procedure in both cases. A hemolytic complication usually needs additional coil embolization or surgical treatment, but in these 2 cases it was successfully treated by haptoglobin infusion to prevent nephropathy and by antiplasmin infusion to promote thrombus formation. Hemolytic complications of coil embolization of PDA can managed by medication when the residual shunt is minimal and the degree of hemolysis is mild.

Prevention of hemoglobinuria by administration of haptoglobin.

This report describes the role of haptoglobin in preventing hemoglobinuria. In rabbits, human haptoglobin administered i.v. worked preventively against the development of hemoglobinuria in spite of the presence of a large amount of hemolysate containing free hemoglobin. More specifically: (1) the kidney did not present a dark brown color, (2) the deposition of iron in the kidney was significantly less than that in the same organ of rabbits given hemolysate only, and (3) the microangiographic and histological findings of the kidney were close to normal patterns. From the above it may be concluded that the administration of haptoglobin is effective for the prevention of hemoglobinuria and subsequent renal damage.

Natriuresis-induced protection in acute myohemoglobinuric renal failure without renal cortical renin content depletion in the rat.

The interrelationships of renal cortical renin content RCRC, sodium chloride excreting and the severity of renal failure were studied in the glycerol-induced acute myohemoglobinuric renal failure model in the rat. Protocols were designed to increase sodium chloride excretion without necessarily resulting in RCRC depletion. Our data fail to demonstrate a relationship between RCRC and severity of renal failure, but they demonstrate an excellent inverse correlation between the sodium chloride excretion of the animals in the 24 h prior to glycerol administration and the severity of resulitng renal failure. The protection of long-term saline-drinking animals should properly be ascribed to the associated natriuresis which develops much before RCRC depletion during the time course of saline drinking. The exact mechanism by which natriuresis exerts its protective effect needs further elucidation, but our data argue against a major role for RCRC in the pathogenesis of acute experimental renal failure.

Effect of lysine on hemolysis-induced kidney damage.

The mechanism of kidney damage commonly seen in patients with intravascular hemolysis is not entirely clear. Injection of distilled water (4 ml within 5 seconds) into the carotid arteries of rats resulted in intravascular hemolysis leading to hemoglobinemia, hemoglobinuria, reduction in inulin clearance, and elevation of urine N-acetyl-beta-D-glucosaminidase (NAG) excretion. When the same experiment was repeated with simultaneous infusion of the positively charged amino acid lysine (30 mmol/L at 3.4 ml/hour), the inulin clearance was unchanged. Urinary NAG excretion was elevated but significantly lower than that in similar rats without lysine infusion. This suggested that lysine protected the kidney from the deleterious effect of hemolysis. Such protection was not observed when the neutral amino acid glycine was infused. Because positively charged but not neutral amino acids are known to inhibit renal protein reabsorption, the protective effect of lysine could be due to inhibition of hemoglobin reabsorption, which might be an important step in the pathogenesis of kidney damage.

Regulation of renal function in thermal injury.

Hypovolemia, low cardiac output, and systemic vasoconstriction are major etiologic factors in acute renal failure occurring in the early postburn period, and elevated levels of stress-related hormones (catecholamines, angiotensin, aldosterone, and vasopressin) are implicated in the mechanism. By counteracting the effects of the hormones, atrial natriuretic polypeptide (ANP) regulates the renal response to burns. ANP was elevated after burns, protecting the kidneys by increasing renal blood flow and urine output. In pulmonary acid injury, increased ANP levels were associated with natriuresis which was reduced by administration of anti-ANP serum. Exogenous ANP given to dogs under constant norepinephrine infusion resulted in improvement of hemodynamic and renal parameters. To prevent tubular damage due to hemoglobinuria, a haptoglobin preparation is administered to patients with extensive third-degree burns. With sufficient fluid replacement, these new treatments will reduce the incidence of acute renal failure in the early postburn period.

Nephrotoxicity of hemoglobin solutions.

Nephrotoxicity is a problem of hemoglobin solutions (HbS) that still awaits full elucidation and correction. Therefore, a study was conducted using five HbS with different characteristics to replace 1/3 of blood volume in five groups of rabbits. All HbS contained bovine Hb, 6.5 g/dl, dissolved into a balanced electrolyte solution. HbS-I was Hb incompletely purified of stromal phospholipids and environmental bacterial endotoxins, and uncrosslinked; HbS-II was pure Hb non crosslinked; HbS-III was completely purified and crosslinked; HbS-IV was like HbS-III, but with pH 8.4; and HbS-V was like HbS-III, with the addition of mannitol. The effects of blood replacement with these solutions were studied on: (a) PAH clearance (expression of renal plasma flow); (b) endogenous creatinine clearance (expression of glomerular filtration); (c) fractional excretion of sodium and (d) urine/plasma osmolarity (expressions of tubular function). Histological changes were assessed after 24 hours. Significant alterations were observed in decrescent order following the administration of HbS-I, -II and -III, while HbS-IV and -V were well tolerated. These results suggest that the nephrotoxicity of Hb solutions can be prevented by the following steps: (1) complete purification of Hb; (2) complete crosslinking; and (3) protection of the kidney by alkalinization of the urine and/or the addition of mannitol.