Miriam Blum

The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations.

OBJECTIVES This study evaluated the prevalence and severity of anemia in patients with congestive heart failure (CHF) and the effect of its correction on cardiac and renal function and hospitalization. BACKGROUND The prevalence and significance of mild anemia in patients with CHF is uncertain, and the role of erythropoietin with intravenous iron supplementation in treating this anemia is unknown. METHODS In a retrospective study, the records of the 142 patients in our CHF clinic were reviewed to find the prevalence and severity of anemia (hemoglobin [Hb] <12 g). In an intervention study, 26 of these patients, despite maximally tolerated therapy of CHF for at least six months, still had had severe CHF and were also anemic. They were treated with subcutaneous erythropoietin and intravenous iron sufficient to increase the Hb to 12 g%. The doses of the CHF medications, except for diuretics, were not changed during the intervention period. RESULTS The prevalence of anemia in the 142 patients increased with the severity of CHF, reaching 79.1% in those with New York Heart Association class IV. In the intervention study, the anemia of the 26 patients was treated for a mean of 7.2 +/- 5.5 months. The mean Hb level and mean left ventricular ejection fraction increased significantly. The mean number of hospitalizations fell by 91.9% compared with a similar period before the study. The New York Heart Association class fell significantly, as did the doses of oral and intravenous furosemide. The rate of fall of the glomerular filtration rate slowed with the treatment. CONCLUSIONS Anemia is very common in CHF and its successful treatment is associated with a significant improvement in cardiac function, functional class, renal function and in a marked fall in the need for diuretics and hospitalization.

The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study

OBJECTIVES This is a randomized controlled study of anemic patients with severe congestive heart failure (CHF) to assess the effect of correction of the anemia on cardiac and renal function and hospitalization. BACKGROUND Although mild anemia occurs frequently in patients with CHF, there is very little information about the effect of correcting it with erythropoietin (EPO) and intravenous iron. METHODS Thirty-two patients with moderate to severe CHF (New York Heart Association [NYHA] class III to IV) who had a left ventricular ejection fraction (LVEF) of < or =40% despite maximally tolerated doses of CHF medications and whose hemoglobin (Hb) levels were persistently between 10.0 and 11.5 g% were randomized into two groups. Group A (16 patients) received subcutaneous EPO and IV iron to increase the level of Hb to at least 12.5 g%. In Group B (16 patients) the anemia was not treated. The doses of all the CHF medications were maintained at the maximally tolerated levels except for oral and intravenous (IV) furosemide, whose doses were increased or decreased according to the clinical need. RESULTS Over a mean of 8.2+/-2.6 months, four patients in Group B and none in Group A died of CHF-related illnesses. The mean NYHA class improved by 42.1% in A and worsened by 11.4% in B. The LVEF increased by 5.5% in A and decreased by 5.4% in B. The serum creatinine did not change in A and increased by 28.6% in B. The need for oral and IV furosemide decreased by 51.3% and 91.3% respectively in A and increased by 28.5% and 28.0% respectively in B. The number of days spent in hospital compared with the same period of time before entering the study decreased by 79.0% in A and increased by 57.6% in B. CONCLUSIONS When anemia in CHF is treated with EPO and IV iron, a marked improvement in cardiac and patient function is seen, associated with less hospitalization and renal impairment and less need for diuretics.

Randomised crossover trial of naltrexone in uraemic pruritus

BACKGROUND Most dialysis patients develop pruritus, for which current treatment is unsatisfactory. Endogenous opioids may be involved in this pruritus. We studied the effect of the opioid antagonist naltrexone on the pruritus of haemodialysis patients. METHODS Naltrexone 50 mg per day by mouth was given to 15 haemodialysis patients with severe resistant pruritus in a randomised, double-blind, placebo-controlled crossover trial. The naltrexone or placebo periods lasted 7 days each with a 7-day washout between the two periods. Pruritus was assessed by the patients on a visual analogue scale from 0 (no pruritus) to 10 (maximum), and mean daily scores were calculated. Plasma histamine and beta-endorphin levels were measured, and spontaneous and stimulated basophil histamine-release were determined. FINDINGS The median pruritus scores at the end of the naltrexone treatment were 2.1 (interquartile range 1.5-2.15) for the naltrexone-placebo sequence and 1.0 (0.4-1.15) for the placebo-naltrexone sequence. The respective values before naltrexone was given were 9.9 (9.85-9.95) and 9.9 (9.3-10.0). Plasma beta-endorphin levels were normal and remained unchanged during the study. Plasma histamine levels were high (mean 2.32 [SD 0.11] ng/mL, normal < 1.0) and decreased after naltrexone (to 1.8 [0.09], p < 0.01). Basophils from haemodialysis patients stimulated by interleukin-3 plus IgE antibodies released high amounts of histamine. The increase was 78.3 (19.3)% compared with 26.6 (16.3)% for five normal controls (p < 0.01). Incubation of the basophils with naloxone, another opioid antagonist, prevented this effect. INTERPRETATION Our data suggest short-term efficacy with few side-effects for the amelioration of uraemic pruritus with naltrexone.

Intravenous iron supplementation for the treatment of the anemia of moderate to severe chronic renal failure patients not receiving dialysis

Iron deficiency may develop in hemodialysis patients, especially when erythropoietin is given. The role of iron deficiency in the anemia of predialysis chronic renal failure (CRF), however, is much less clear. We have intravenously (IV) administered iron as ferric saccharate in a total dose of 200 mg elemental iron monthly for 5 months to 33 CRF patients who remained anemic despite oral iron supplementation and who had no laboratory signs of iron overload. None was receiving erythropoietin therapy. In 22 of the patients there was an increase in the hematocrit values by the end of the study. These patients were considered responders to intravenous iron (IV Fe) therapy. In 11 patients the iron administration was not associated with improvement of the anemia (nonresponders). Before onset of the IV Fe therapy there were no differences between the responders and nonresponders with regard to degree of anemia, serum ferritin, iron saturation, renal function, or blood pressure. One additional patient was excluded from the study because of a mild reaction during an IV test dose before the study. No worsening of kidney function and no other side effects were noted. In four patients (three responders and one nonresponder) the control of blood pressure necessitated antihypertensive drug therapy adjustment. In conclusion, IV Fe supplementation in two thirds of anemic CRF patients not receiving dialysis resulted in a significant improvement of the anemia, thus avoiding the necessity of erythropoietin or blood administration. This could be achieved by increasing the plasma ferritin levels to 200 to 400 microns/L and/or increasing the iron saturation to 25% to 35%. Intravenous ferric saccharate appears to be a safe and effective method of administering iron for the correction of anemia in CRF patients not receiving dialysis.

The association between congestive heart failure and chronic renal disease.

Purpose of reviewRecent findings on the relationship between congestive heart failure and renal failure are summarized in this review. Recent findingsCongestive heart failure is found in about one-quarter of cases of chronic kidney disease. The most common cause of congestive heart failure is ischemic heart disease. The prevalence of congestive heart failure increases greatly as the patients renal function deteriorates, and, at end-stage renal disease, can reach 65-70%. There is mounting evidence that chronic kidney disease itself is a major contributor to severe cardiac damage and, conversely, that congestive heart failure is a major cause of progressive chronic kidney disease. Uncontrolled congestive heart failure is often associated with a rapid fall in renal function and adequate control of congestive heart failure can prevent this. The opposite is also true: treatment of chronic kidney disease can prevent congestive heart failure. There is new evidence showing the cardioprotective effect of carvedilol in patients on dialysis, and of simvastatin and eplerenone in patients with congestive heart failure. Use of non-steroidal anti-inflammatory drugs doubles the rate of hospitalization in patients with congestive heart failure. Anemia has been found in one-third to half the cases of congestive heart failure, and may be caused not only by chronic kidney disease but by the congestive heart failure itself. The anemia is associated with worsening cardiac and renal status and often with signs of malnutrition. Control of the anemia and aggressive use of the recommended medication for congestive heart failure may improve the cardiac function, patient function and exercise capacity, stabilize the renal function, reduce hospitalization and improve quality of life. Congestive heart failure, chronic kidney disease and anemia therefore appear to act together in a vicious circle in which each condition causes or exacerbates the other. Both congestive heart failure and anemia are often undertreated. Cooperation between nephrologists and other physicians in the treatment of patients with anemic congestive heart failure may improve the quality of care and the subsequent prognosis for both congestive heart failure and chronic kidney disease. SummaryAdequate and early detection and aggressive treatment of congestive heart failure and chronic kidney disease and the associated anemia may markedly slow the progression of both diseases.

Intravenous Ferric Saccharate as an Iron Supplement in Dialysis Patients

In the present prospective study we examined the long-term effect of intravenous supplementation with ferric saccharate (IV Fe) in the treatment of the anemia of chronic dialysis patients. All patients, 64 on chronic hemodialysis (HD) and 9 on chronic ambulatory peritoneal dialysis (CAPD), were treated intravenously with this preparation in a dose of 100 mg elemental iron twice monthly. There were five groups. Group 1: 41 HD patients who were receiving erythropoietin (EPO) for at least 6 months prior to the addition of IV Fe. In this group, when IV Fe was given over 6 months, the hematocrit (Hct) increased from a mean of 28.7 to 33.7%. Over the next 6 months, the EPO dose was gradually reduced by a mean of 61.1%, but the mean Hct remained unchanged. Group 2: 11 HD patients who started IV EPO simultaneously with the IV Fe. In this group, over 6 months, the mean Hct increased from 28.1 to 34.1. Over the next 6 months, the EPO dose was gradually reduced by 75.7%, but the mean Hct remained unchanged. Group 3: 12 HD patients who received IV Fe alone for 12 months. The mean Hct increased from 30.5 to 37.9%. Group 4: 4 CAPD patients who had been receiving subcutaneous EPO for at least 6 months prior to IV Fe therapy. Over the subsequent 6 months of IV Fe, the mean Hct increased from 28.4 to 33.3%. Group 5: 5 CAPD patients not on EPO who received IV Fe for 6 months. The mean Hct increased from 27.7 to 35.6%. No adverse effects were seen in any patients throughout the study. In conclusion, adequate Fe supplementation may allow the target Hct of about 33% to be reached without, or with only very low doses of EPO. IV Fe as ferric saccharate is a new and safe form of parenteral iron therapy of the anemia of chronic dialysis patients.

Low Nitric Oxide Production in Patients with Chronic Renal Failure

Background: Rats with chronic renal failure have a low nitric oxide (NO) production and a diminished NO excretion. The supplementation of L-arginine has an inhibitory effect on the progression of renal insufficiency. Methods: The present study was designed to determine whether chronic renal failure patients have a low NO production. Plasma and urine nitrate (NO3) and nitrite (NO2), stable metabolites of NO, were measured in 83 consecutive patients with chronic renal failure. The 83 chronic renal failure patients were divided into three groups: group 1, mild renal failure (creatinine clearance >60 ml/min/1.73 m2); group 2, moderate renal failure (creatinine clearance >30 <60 ml/min/1.73 m2), and group 3, severe renal failure (creatinine clearance <30 ml/min/1.73 m2). Thirty-three healthy volunteers served as controls. Results: The daily urinary NO excretion was significantly lower in patients with moderate and severe renal failure as compared with those with mild renal failure and normal controls. The lowest values were found in the severe renal failure group. When the 24-hour urinary NO excretion or NO per milligram creatinine and the NO clearance were correlated with the renal function in all patients as a group, these parameters were directly correlated with the creatinine clearance and inversely correlated with the serum creatinine level. The plasma NO concentration was not different between the three chronic renal failure groups, but higher than in the controls. Plasma NO in renal failure patients was not correlated with the creatinine clearance or serum creatinine levels. Conclusions: Chronic renal failure is a state of NO deficiency. Treatment strategies to increase NO production (L-arginine supplementation or other NO compounds) may prove to be useful in maintaining the renal function and slow the progression of renal disease.

Improvement of cardiac performance by intravenous infusion of l-arginine in patients with moderate congestive heart failure

OBJECTIVES The aim of this study was to evaluate the hemodynamic effect of L-arginine infusion in patients with congestive heart failure. BACKGROUND Endothelium-dependent vasodilation is impaired in patients with congestive heart failure. Nitric oxide, which was identified as endothelium-derived relaxing factor, is generated by nitric oxide synthase from L-arginine. Our hypothesis was that administration of L-arginine in patients with congestive heart failure may increase nitric oxide production and have a beneficial hemodynamic effect. METHODS Twelve patients with congestive heart failure (New York Heart Association class II or III) due to coronary artery disease (left ventricular ejection fraction < 35%) were given 20 g of L-arginine by intravenous infusion over 1 h at a constant rate. Stroke volume, cardiac output and left ventricular ejection fraction were determined with Doppler echocardiography at baseline and at 30 and 60 min and 1 h after the end of infusion. Blood and urinary levels of nitrite/nitrate (NO2/NO3), stable metabolites of nitric oxide, were measured and clearance was calculated. RESULTS One hour of infusion of L-arginine resulted in a significant increase in stroke volume (from 68 +/- 18 ml to 76 +/- 23 ml [mean +/- SD], p = 0.014) and cardiac output (from 4.07 +/- 1.22 liters/min to 4.7 +/- 1.42 liters/min, p = 0.006) without a change in heart rate. Mean arterial blood pressure decreased (from 102 +/- 11 mm Hg to 89 +/- 9.5 mm Hg, p < 0.002), and systemic vascular resistance decreased significantly. Within 1 h after cessation of L-arginine infusion, blood pressure, stroke volume, cardiac output and systemic vascular resistance were statistically not different from baseline values. Clearance of NO2/NO3 increased significantly during L-arginine administration (from 13.28 +/- 0.42 ml/min to 29.97 +/- 1.09 ml/min, p < 0.001). CONCLUSIONS Infusion of L-arginine in patients with congestive heart failure results in increased production of nitric oxide, peripheral vasodilation and increased cardiac output, suggesting a beneficial hemodynamic and possibly therapeutic profile.

Comparison of a Vegetable-Based (Soya) and an Animal-Based Low-Protein Diet in Predialysis Chronic Renal Failure Patients

There is some experimental evidence to suggest that progression of chronic renal failure (CRF) is slower on diets based on soya protein than on diets based on animal protein. We have compared the effect of a soya-based vegetarian low-protein diet (VPD) and an animal-based low-protein diet (APD) in 15 patients with CRF. 15 patients with CRF (51Cr-EDTA-measured glomerular filtration rate 15–50 ml/min/1.73 m2) were studied. In a randomized crossover trial, the patients were given each diet (each containing 0.75 g protein and 32 kcal per kilogram body weight) for a 6-month period. Nine patients completed the trial, 2 others dropped out because they could not tolerate the VPD, 3 because of unrelated medical complications, and 1 for technical reasons. The caloric intake was higher and the protein, phosphate and essential amino acid intake lower on the VPD than on the APD. The compliance with the suggested caloric intake was better with the VPD than with the APD (97 vs. 88% of recommended intake), as was the compliance with the suggested protein intake (94 vs. 112% of recommended intake) and with the suggested phosphate intake (102 vs. 116%). The mean glomerular filtration rate, as judged by 51Cr-EDTA, was similar after 6 months on each diet and remained unchanged throughout the entire year of the study. The rate of fall of glomerular filtration, as measured by the slope of 1/serum creatinine was slowed by 73% during the 1-year study period as compared with the prestudy period. Nutritional status (as measured by body mass index, midarm circumference, and lean body mass and percent body fat), serum transferrin, cholesterol and albumin, and total lymphocyte count were similar on the two diets. The serum albumin level on both diets, however, was significantly higher on the two diets than during the prediet period. Blood urea nitrogen, urine urea nitrogen, protein catabolic rate, and 24-hour urine creatinine and phosphate were lower on the VPD than on the APD. The 24-hour protein excretion was similar on the two diets. The two low-protein diets resulted in a slowing in the progression of CRF. A VPD is well tolerated in CRF and is associated with lower protein and phosphate intakes and a higher caloric intake than an APD and may, therefore, be used as a safe alternative or partial substitute for the usual APD in CRF.

The Interaction between Heart Failure, Renal Failure and Anemia – The Cardio-Renal Anemia Syndrome

Background: Many patients with congestive heart failure (CHF) have chronic kidney insufficiency (CKI) and anemia. Aims: The purpose of this review is to clarify the relationship between these three factors and to study the effect of correction of anemia in CHF and CKI. Findings: Anemia, CHF and CKI are each capable of causing or worsening each other. Thus they form a vicious circle which can result in progressive CHF, CKI and anemia. Aggressive therapy of CHF, CKI and control of the associated anemia with erythropoietin and i.v. iron can prevent the progression of CHF and CKI, reduce hospitalization, and improve quality of life. Conclusion: CHF patients are a major source of end-stage renal failure patients and deserve special attention. If treated well and early, progressive heart failure and renal failure can be prevented. Cooperation between nephrologists, cardiologists, and other internists will improve the care of all three conditions and prevent their progression.