Delayed administration of darbepoetin or erythropoietin protects against ischemic acute renal injury and failure

Administration of human recombinant erythropoietin (EPO) at time of acute ischemic renal injury (IRI) inhibits apoptosis, enhances tubular epithelial regeneration, and promotes renal functional recovery. The present study aimed to determine whether darbepoetin-alfa (DPO) exhibits comparable renoprotection to that afforded by EPO, whether pro or antiapoptotic Bcl-2 proteins are involved, and whether delayed administration of EPO or DPO 6 h following IRI ameliorates renal dysfunction. The model of IRI involved bilateral renal artery occlusion for 45 min in rats (N = 4 per group), followed by reperfusion for 1-7 days. Controls were sham-operated. Rats were treated at time of ischemia or sham operation (T0), or post-treated (6 h after the onset of reperfusion, T6) with EPO (5000 IU/kg), DPO (25 mug/kg), or appropriate vehicle by intraperitoneal injection. Renal function, structure, and immunohistochemistry for Bcl-2, Bcl-XL, and Bax were analyzed. DPO or EPO at T0 significantly abrogated renal dysfunction in IRI animals (serum creatinine for IRI 0.17 +/- 0.05 mmol/l vs DPO-IRI 0.08 +/- 0.03 mmol/l vs EPO-IRI 0.04 +/- 0.01 mmol/l, P = 0.01). Delayed administration of DPO or EPO (T6) also significantly abrogated subsequent renal dysfunction (serum creatinine for IRI 0.17 +/- 0.05 mmol/l vs DPO-IRI 0.06 +/- 0.01 mmol/l vs EPO-IRI 0.03 +/- 0.03 mmol/l, P = 0.01). There was also significantly decreased tissue injury (apoptosis, P < 0.05), decreased proapoptotic Bax, and increased regenerative capacity, especially in the outer stripe of the outer medulla, with DPO or EPO at T0 or T6. These results reaffirm the potential clinical application of DPO and EPO as novel renoprotective agents for patients at risk of ischemic acute renal failure or after having sustained an ischemic renal insult.     

Erythropoietin protects against ischaemic acute renal injury.

BACKGROUND: Erythropoietin (EPO) has recently been shown to exert important cytoprotective and anti-apoptotic effects in experimental brain injury and cisplatin-induced nephrotoxicity. The aim of the present study was to determine whether EPO administration is also renoprotective in both in vitro and in vivo models of ischaemic acute renal failure. METHODS: Primary cultures of human proximal tubule cells (PTCs) were exposed to either vehicle or EPO (6.25-400 IU/ml) in the presence of hypoxia (1% O(2)), normoxia (21% O(2)) or hypoxia followed by normoxia for up to 24 h. The end-points evaluated included cell apoptosis (morphology and in situ end labelling [ISEL], viability [lactate dehydrogenase (LDH release)], cell proliferation [proliferating cell nuclear antigen (PCNA)] and DNA synthesis (thymidine incorporation). The effects of EPO pre-treatment (5000 U/kg) on renal morphology and function were also studied in rat models of unilateral and bilateral ischaemia-reperfusion (IR) injury. RESULTS: In the in vitro model, hypoxia (1% O(2)) induced a significant degree of PTC apoptosis, which was substantially reduced by co-incubation with EPO at 24 h (vehicle 2.5+/-0.5% vs 25 IU/ml EPO 1.8+/-0.4% vs 200 IU/ml EPO 0.9+/-0.2%, n = 9, P<0.05). At high concentrations (400 IU/ml), EPO also stimulated thymidine incorporation in cells exposed to hypoxia with or without subsequent normoxia. LDH release was not significantly affected. In the unilateral IR model, EPO pre-treatment significantly attenuated outer medullary thick ascending limb (TAL) apoptosis (EPO 2.2+/-1.0% of cells vs vehicle 6.5+/-2.2%, P<0.05, n = 5) and potentiated mitosis (EPO 1.1+/-0.3% vs vehicle 0.5+/-0.3%, respectively, P<0.05) within 24 h. EPO-treated rats exhibited enhanced PCNA staining within the proximal straight tubule (6.9+/-0.7% vs vehicle 2.4+/-0.5% vs sham 0.3+/-0.2%, P<0.05), proximal convoluted tubule (2.3+/-0.6% vs vehicle 1.1+/-0.3% vs sham 1.2+/-0.3%, P<0.05) and TAL (4.7+/-0.9% vs vehicle 0.6+/-0.3% vs sham 0.3+/-0.2%, P<0.05). The frequency of tubular profiles with luminal cast material was also reduced (32.0+/-1.6 vs vehicle 37.0+/-1.3%, P = 0.05). EPO-treated rats subjected to bilateral IR injury exhibited similar histological improvements to the unilateral IR injury model, as well as significantly lower peak plasma creatinine concentrations than their vehicle-treated controls (0.04+/-0.01 vs 0.21+/-0.08 mmol/l, respectively, P<0.05). EPO had no effect on renal function in sham-operated controls. CONCLUSIONS: The results suggest that, in addition to its well-known erythropoietic effects, EPO inhibits apoptotic cell death, enhances tubular epithelial regeneration and promotes renal functional recovery in hypoxic or ischaemic acute renal injury.     

Erythropoietin ameliorates renal dysfunction during endotoxaemia.

BACKGROUND: Sepsis has a high mortality (50-80%) when associated with acute renal failure (ARF). Oxidant injury and proinflammatory cytokines and chemokines have been shown to increase with endotoxaemia-related ARF. Since erythropoietin (EPO) has been demonstrated to possess anti-oxidant and anti-inflammatory properties, EPO may have therapeutic efficacy for treating ARF associated with endotoxaemia. METHODS: Wild-type mice were given 2.5 mg/kg of intraperitoneal (i.p.) endotoxin, lipopolysaccharide (LPS), and studied 16 h later. Thirty minutes prior to LPS, the mice were given either EPO or vehicle. RESULTS: During endotoxaemia, EPO was found to significantly attenuate the renal dysfunction, as assessed by glomerular filtration rate (48.1 +/- 12.4 microl/min vs 136.7 +/- 30.2, P < 0.05). Renal blood flow and mean arterial pressure were not significantly different between the two groups. The renal dysfunction during endotoxaemia was associated with a decrease in renal superoxide dismutase (SOD). The EPO-related renal protection was associated with reversal of the effects of endotoxin on renal SOD. CONCLUSION: This is the first demonstration of a renal protective effect of EPO on endotoxin-related renal dysfunction.     

Peritoneovenous shunt in the management of the hepatorenal syndrome

The hepatorenal syndrome (HRS) is a terminal complication of severe liver disease associated with a mortality of 80 to 90%. Although the renal functional abnormalities in the HRS suggest prerenal azotemia, volume expansion with saline, albumin or ascitic fluid rarely results in reversal of the HRS because fluid redistributes from the vascular space. Since the peritoneovenous (PV) shunt causes sustained central volume expansion, it has been advocated for the treatment of the HRS. We prospectively compared the PV shunt (N = 10) to Medical Therapy (MED) (N = 10) on renal function and mortality in 20 patients with the HRS associated with alcoholic liver disease. The HRS was diagnosed on the basis of clinical, hemodynamic, and laboratory criteria. The insertion of a PV shunt resulted in an increase in pulmonary capillary wedge pressure (4.2 +/- 1.1 vs. -1.5 +/- 1.0 mm Hg, P less than 0.01) and in cardiac index (0.8 +/- 0.3 vs. -0.2 +/- 0.3 1/min/m2, P less than 0.05). After 48 to 72 hours, weight (+3.1 +/- 1.1 kg) and serum creatinine (3.9 +/- 0.5 to 5.5 +/- 0.7 mg/dl, P less than 0.001) were increased with MED therapy and decreased (weight: -3.7 +/- 0.7 kg; serum creatinine: 3.6 +/- 0.4 to 3.0 +/- 0.5, P less than 0.05) with the PV shunt. Despite improvement in renal function, only one patient with the PV shunt had prolonged survival (210 days). In the remainder, survival was 13.8 +/- 2.2 days compared to 4.1 +/- 0.6 days with MED therapy. We conclude that the PV shunt often stabilizes renal function, but does not prolong life in patients with the HRS.     

Renal blood flow in experimental septic acute renal failure

Reduced renal blood flow (RBF) is considered central to the pathogenesis of septic acute renal failure (ARF). However, no controlled experimental studies have continuously assessed RBF during the development of severe septic ARF. We conducted a sequential animal study in seven female Merino sheep. Flow probes were implanted around the pulmonary and left renal arteries. Two weeks later, systemic hemodynamics and RBF were monitored continuously during a 48-h control period and, after a week, during a 48-h period of hyperdynamic sepsis induced by continuous Escherichia coli infusion. Infusion of E. coli induced hyperdynamic sepsis with significantly increased cardiac output (3.8+/-0.4 vs 9.8+/-1.1 l/min; P<0.05), decreased mean arterial pressure (89.2+/-3.2 vs 64.3+/-5.3 mm Hg; P<0.05), and increased total peripheral conductance (42.8+/-3.5 in controls vs 153.7+/-24.7 ml/min/mm Hg in septic animals; P<0.05). Hyperdynamic sepsis was associated with marked renal vasodilatation (renal conductance: 3.0+/-0.7 vs 11.4+/-3.4 ml/min/mm Hg; P<0.05) and a marked increase in RBF (262.3+/-47.7 vs 757.4+/-250.1 ml/min; P<0.05). Serum creatinine increased over 48 h (73+/-18 vs 305+/- micromol/l; P<0.05) whereas creatinine clearance decreased (95.5+/-25.9 vs 20.1+/-19.3 ml/min; P<0.05). After 24 h, urine output decreased from 1.4 to 0.3 ml/kg/h (P<0.05). Infusion of E. coli induced hyperdynamic sepsis and ARF. Septic ARF in this setting was associated with a marked increase in RBF and with renal vasodilatation.     

Supplemented very low protein diet ameliorates responsiveness to erythropoietin in chronic renal failure

BACKGROUND: The aim of this study was to evaluate the relationship between uremic state and erythropoiesis in patients with predialytic chronic renal failure (CRF). METHODS: We monitored for 2 years the erythropoietin (EPO) requirement in patients with advanced CRF (creatinine clearance < or =25 mL/min), randomized to either low protein diet (LPD) group (0.6 g/kg body weight/day, N = 10) or very low protein diet (VLPD) group (0.3 g/kg body weight/day, N = 10) supplemented with a mixture of ketoanalogs and essential amino acids, both kept at target hemoglobin levels. RESULTS: The achieved protein intake after 6 months was 0.79 +/- 0.02 g/kg body weight/day and 0.50 +/- 0.02 g/kg body weight/day in LPD and VLPD, respectively; such a difference was maintained up to the end of follow up. The final hemoglobin values did not differ from the basal values in either group (11.5 +/- 0.2 g/dL and 11.5 +/- 0.3 g/dL). EPO dose, that was similar at baseline (62.4 +/- 9.6 UI/kg body weight/week and 61.8 +/- 8.8 UI/kg body weight/week subcutaneously), remained unchanged in LPD but progressively decreased in VLPD down to the final value of 41.2 +/- 7.0 UI/kg body weight/week (P < 0.0001 vs. basal and LPD). VLPD was associated with a decrease of urinary excretion and serum levels of urea nitrogen and phosphate; however, EPO requirement was not correlated with the changes of these parameters. On the contrary, the variation of EPO dose directly correlated with the modification of parathyroid hormone (PTH) levels, that diminished from 229 +/- 55 pg/mL to 118 +/- 16 pg/mL (P < 0.0001) in VLPD and did not change in LPD. CONCLUSION: In patients with advanced CRF, an effective decrease of protein intake of 0.3 g/kg body weight/day induces a reduction of about 35% of the EPO dose required to maintain the target hemoglobin levels. This effect appears dependent on the correction of a moderate secondary hyperparathyroidism.     

Effect of vitamin D metabolites on calcitriol metabolism in experimental renal failure

Previous studies from our laboratory have demonstrated that metabolic clearance rate (MCR) of calcitriol is decreased in experimental renal failure. In this experiment, we examined the effects of calcitriol, 25-hydroxyvitamin D3 (25(OH)D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) on the MCR of calcitriol in renal failure produced in rats by partial nephrectomy. The MCR of calcitriol in these rats with renal failure was significantly lower than in control rats with sham operations. Plasma concentrations of calcitriol did not differ between the rats with moderate renal failure and control rats (sham, 74.7 +/- 3.6 pg/ml, N = 7; renal failure, 67.7 +/- 6.0, N = 6; serum creatinine 0.56 +/- 0.02 mg/dl vs. 0.96 +/- 0.02); however, the levels were significantly lower in rats with severe renal failure (sham, 66.5 +/- 5.1 pg/ml, N = 7, severe renal failure, 49.6 +/- 2.1 pg/ml, N = 8; serum creatinine 0.53 +/- 0.01 mg/dl vs. 1.40 +/- 0.03). Subcutaneous infusion of calcitriol (10 ng/kg/day) in rats with severe renal failure for one week significantly increased the MCR of calcitriol (0.22 +/- .01 vs. 0.17 +/- .01 ml/min/kg, P less than 0.001). Infusion of 25(OH)D3 (600 ng/day) or 24,25(OH)2D3 (1 microgram/day) in rats with renal failure for one week also increased the MCR of calcitriol (25(OH)D3, 0.25 +/- 0.01 ml/min/kg; 24,25(OH)2D3, 0.25 +/- 0.01, both P less than 0.001) when compared to rats with renal failure infused with vehicle (0.21 +/- 0.01). Administration of 24,25(OH)2D3 significantly lowered the plasma levels of calcitriol in rats with renal failure (52.3 +/- 3.1 pg/ml, P less than 0.05) in comparison to the rats with renal failure infused with vehicle (67.7 +/- 6.0).(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficacy of erythropoietin administration in the treatment of anemia immediately after renal transplantation

Anemia negatively impacts cardiovascular comorbidity and hospitalization. In animals, recombinant erythropoietin (RhuEPO) leads to faster recovery after acute tubular necrosis. This study evaluates the effect of RhuEPO (Recormon, Hoffman-La Roche, Basel, Switzerland) on the correction of anemia and kidney function after renal transplantation. Patients receiving a renal transplant were randomized to receive or not receive RhuEPO 100 U/kg three times per week if the hemoglobin (Hb) level was less than 12.5 g/dL. The time to reach an Hb level greater than 12.5 g/dL was 66.5+/-14.5 days versus 52.6+/-23.7 days in the non-EPO and EPO groups, respectively (P=0.05). After 3 months, Hb levels were not different between the non-EPO and EPO groups (12.6+/-1.5 g/dL vs. 12.0+/-1.5 g/dL, respectively), although there was a higher increase in the EPO group (4.1+/-1.1 g/dL vs. 3.2+/-1.1 g/dL, P=0.02). In a Cox regression analysis, EPO use (relative risk 7.2, P=0.004) and dose (relative risk=0.63, P=0.04) were retained as independent variables predicting the time to reach an Hb level greater than 12.5 g/dL. In the EPO group, 14 of 22 patients reached the target Hb level of more than 12.5 g/dL versus 12 of 18 patients in the non-EPO group (P=not significant). Serum creatinine levels were not different between groups. RhuEPO in the immediate posttransplantation period seems to have no relevant clinical impact on the correction of anemia. There was no difference in the evolution of serum creatinine levels. In view of the cost, the use of RhuEpo in the posttransplantation period should be limited to high-risk patients.     

Erythropoietin treatment in the sixth posttransplant month as a prognostic factor for renal allograft survival

The purpose of this work was to assess the prognostic value of the need for erythropoietin (EPO) treatment at 6 months after transplantation. We retrospectively reviewed the outcomes of 143 consecutive cadaveric kidney transplants performed between January 2000 and April 2004, functioning at 6 months postransplantation. Patients were divided into two groups: group EPO6m (n = 24) received EPO treatment in the sixth month, and a control group (n = 119) did not receive EPO. Renal function deterioration (RFD) was considered to be a sustained decrease in creatinine clearance (CrCl) greater than 20% between the sixth month postransplant and the last visit. Mean follow-up was 38 +/- 16 months. The mean ages of the donor (57 +/- 9 vs 49 +/- 12 years; P = .001) and the recipient (59 +/- 12 vs 47 +/- 17 years; P = .000) were greater in the EPO6m group. Delayed graft function (83% vs 48%; P = .001) was more frequent in the EPO6m group. At 6 months after transplantation the EPO6m group showed lower hemoglobin (11.52 +/- 1.71 vs 13.32 +/- 1.69 g/dL; P = .000), higher serum creatinine (2.31 +/- 0.72 vs 1.65 +/- 0.53 mg/dL; P = .000), lower CrCl (33.53 +/- 10.83 vs 53.6 +/- 17.58 mL/min; P = .000), and similar proteinuria. RFD was more common in the EPO6m group (38% vs 10%; P = .026), with a different pattern of evolution of CrCl (-0.098 +/- 0.176 vs +0.093 +/- 0.396 mL/min/mo, P = .000). Multivariate analysis demonstrated that treatment with EPO at 6 months was the only predictor of RFD (RR 4.46; 1.58 to 12.58; P = .005). The need for EPO at 6 months postransplant was a good predictor of later renal allograft deterioration, more sensitive than serum creatinine or proteinuria.     

Serum erythropoietin levels and their correlation with the erythropoietic system in hemodialysis patients and renal allograft recipients

BACKGROUND: Following renal transplantation, serum erythropoietin (EPO) levels gradually increase during the first 2 to 3 months. However, some transplant recipients continue to remain anemic. The aim of the present study was to correlate serum EPO concentrations with hematocrit (Hct) and hemoglobin (Hb) levels in hemodialysis (HD) patients and renal allograft recipients. METHODS: In a comparative cross-sectional study, serum EPO concentrations and Hb and Hct levels were measured in 35 chronic HD patients and 40 transplant recipients who had stable kidney function for at least 6 months after transplantation (group 1). The HD patients were further divided based on their recombinant human (rHu) EPO supplementation into those who received rHu EPO during dialysis (group 2A, n=15) and those who were not on rHu EPO (group 2B, n=20). Data are presented as mean values +/- SD. The statistical analysis was performed by SPSS version 11.0 using chi-square, ANOVA, and Pearson correlation tests. A general linear model (GLM) was used to compensate for the effects of age. The P value for significance was set at .05. RESULTS: Group 2B patients tended to be older than groups 1 and 2A (P=.014). The sex ratios were comparable among groups. Mean EPO level was 17.09 +/- 10.99 mIU/mL in recipients, which was comparable with that of HD patients (18.54 +/- 26.18 mIU/mL; P>.05). No significant correlation was observed between the serum EPO concentrations and Hb and Hct levels in recipients (P>.05). When comparing the 3 groups, EPO was not correlated with Hct and Hb in any group. Hb and Hct were significantly higher among HD patients not on rHu EPO therapy (P=.02). GLM, with age as a covariate, did not yield a significant difference between EPO levels of the studied groups (P=.36). CONCLUSIONS: This study showed that serum EPO level was in the normal range in recipients and HD patients. We were not able to find any correlation between Hb and Hct levels and EPO concentrations in any group of patients irrespective of rHu EPO supplementation. Hence, impaired EPO stimulatory effects may be considered a potential contributor to anemia in these patients.     

Microcytic anemia secondary to intraperitoneal aluminum in normal and uremic rats

Dialysis patients exposed to high aluminum (Al) dialysate develop a microcytic anemia which is reversed by deionization (DI) of the dialysate. Because DI removes substances in addition to Al which are known to cause anemia, these experiments were undertaken to determine if Al causes anemia and if the anemia of uremia can be enhanced by Al. Four groups of rats were studied: sham control (A) N = 6; uremic control (B) N = 6; Al-loaded non-uremic (C) N = 7; and Al-loaded uremic (D) N = 5. Aluminum treatment was 1 mg Al intraperitoneally daily for 6 weeks. Uremic rats (B+D) were 1 5/6 nephrectomized; non-uremic (A+C) were sham-operated. Blood samples (200 microliter) were obtained prior to (C1) and weekly during treatment (T1 to T6) and analyzed by Coulter Counter. No significant difference in hemoglobin (Hb), hematocrit (Hct), or mean cell volume (MCV) was noted at C1 X At T3, MCV of Al-treated rats (C+D) was significantly less than sham control (A) (55.1 +/- 0.5 and 53.0 +/- 0.8 vs. 60.8 +/- 1.5 mu3, P less than 0.05). At T6, MCV, Hb, and Hct of Al-loaded uremic rats (D) (49 +/- 0.5 mu3; 11.8 +/- 0.5 g/dl; 25.1 +/- 2%) were significantly less than both A (58.6 +/- 1.3 mu3; 16.1 +/- 0.4 g/dl; 44.8 +/- 0.3%) and B (58.7 +/- 1.4 mu3; 13.8 +/- 0.4 g/dl; 33.6 +/- 0.5%) (P less than 0.05) and MCV, Hb, and Hct of Al-loaded non-uremic rats (C) (51.7 +/- 1.7 mu3; 12.6 +/- 0.3 g/dl; 29.4 +/- 1.5%) was significantly less than A (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Evolution of hepatorenal syndrome after orthotopic liver transplantation: comparative analysis with patients who developed acute renal failure in the early postoperative period of liver transplantation

OBJECTIVE: The purpose of this study was to ascertain the prognosis of patients with hepatorenal syndrome (HS) prior to orthotopic liver transplantation (OLT) by comparisons with a group of selected patients with normal renal function (NRF) pretransplantation who developed acute renal failure (ARF) in the early postoperative period. MATERIALS AND METHODS: Fifty-two OLT cases developed ARF in the early postoperative period between March 1999 and October 2004; 17 cases experienced HS prior to OLT. ARF was defined as serum creatinine level (Cr) >1.5 mg/dL or a creatinine clearance (CrCl) <50 mL/min. The immunosuppressive therapy was the same in both groups: low doses of tacrolimus were prescribed to reach trough levels of 5 ng/mL in the first week after OLT, where patients were administered monoclonal antibodies and corticosteroids. RESULTS: No differences were observed between the groups for gender, age or APACHE II Score in the first 24 hours after OLT. Patients with HS pretransplantation showed higher Cr and urea (U) levels than the other group (Cr: 2.1 +/- 0.8 HS vs 0.9 +/- 0.2, P = .000; U: 93.6 +/- 51.9 HS vs 42.1 +/- 19.3, P = .001). The ICU days of stay were similar (12.8 +/- 0.5 HS vs 19.7 +/- 15.2, P = .053). At the end of 1 year follow-up after OLT there were no differences in mortality (35% HS vs 26%), need for renal replacement therapy (23% HS vs 34%), infection (59% HS vs 51%), or rejection (6% HS vs 29%, P = .06). CONCLUSIONS: Patients with HS prior to OLT showed a similar prognosis to a group of selected patients with NRF pretransplantation, but developed ARF in the early postoperative period which was treated with monoclonal antibodies and low doses of tacrolimus.     

Continuous venovenous hemodialysis treatment in critically ill patients after liver transplantation

BACKGROUND: Acute renal failure (ARF) in critically ill patients is associated with a high mortality rate. Continuous renal replacement therapy (CRRT) is now widely used for the treatment of ARF in these critically ill patients. We retrospectively analyzed the role of CRRT as a prognostic parameter in patients receiving a cadaveric liver graft in 1998. METHODS: We reviewed the patient records of all adult recipients of a cadaveric liver graft (N = 54) in 1998 and compared those who underwent CRRT treatment (N = 19) to those without CRRT treatment (N = 35). RESULTS: Mortality was high in the continuous venovenous hemodialysis (CVVHD) group (58%). At the time of transplantation, creatinine (1.7+/-0.4 vs. 1.0+/-0.1 mg/dl), blood urea nitrogen (40+/-13 vs. 22+/-3 mg/dl), aspartate aminotransferase (ASAT; 585+/-420 vs. 242+/-97 U/liter), and bilirubin (11.6+/-4.1 vs. 6.5+/-1.9 mg/dl) were higher in the CVVHD group than in controls, whereas hemoglobin (10.3+/-0.6 vs. 10.8+/-0.4 g/dl), white blood cells (6.3+/-0.6 vs. 7.0+/-0.8/nl), and thrombocytes (110+/-18 vs. 90+/-10/nl) were similar. After transplantation, liver graft function was impaired in the CVVHD group as compared with controls. CONCLUSIONS: The necessity for CRRT in patients after liver transplantation correlates with a high risk of death. Thus, more efforts have to be made to prevent renal failure in patients after liver transplantation.     

Augmented aldosterone and insulin responses to potassium infusion in dogs with renal failure

The present study examines acute potassium-induced insulin and aldosterone responses in renal failure, and the role of chronic dietary potassium intake in modifying these acute responses. Plasma aldosterone (PA) and insulin (IRI) responses to acute KCl infusion were examined in control and remnant kidney dogs on two potassium intakes. Dogs (N = 8) received the KCl infusions after 10 days of a 60, and then 10 days of a 200, mEq daily potassium intake during control and after surgical-induced renal failure (CRF). A one hour intravenous infusion of KCl (2 mEq KCl/kg/hr) in dextrose and water was performed with blood samples for PA, IRI, creatinine and electrolytes, and urine for electrolytes and creatinine at 20 minute intervals one hour preceding, during, and after the infusion. Preinfusion PA was higher (P less than 0.05) in controls and CRF dogs on 200 mEq potassium intake compared to 60 mEq potassium intake. The peak incremental responses of PA to KCl infusion were increased (P less than 0.01) in CRF compared to controls on 60 mEq (PA 36 +/- 4.2 vs. 26 +/- 3.0 ng/dl) and 200 mEq (delta PA 49 +/- 5.6 vs. 37 +/- 2.8 ng/dl) potassium intakes. Differences in incremental PA responses in CRF were not due to altered aldosterone metabolic clearance rates, changes in renin, or ACTH activity. Pre-infusion IRI was higher (P less than 0.05) in CRF than control dogs on both potassium diets.(ABSTRACT TRUNCATED AT 250 WORDS)     

Factors influencing calcitriol metabolism in renal failure

Metabolic clearance rate (MCR) and production rate (PR) of calcitriol is decreased in experimental renal failure. In this experiment, we studied uremia and secondary hyperparathyroidism as possible causes of the abnormal calcitriol metabolism. Normal rats were made uremic by infusing phosphorus-free urine for 24 hours. Both the MCR (0.22 +/- 0.01 ml/min/kg, N = 6 P less than 0.001) and the PR (16.6 +/- 1.97 ng/kg/day, P less than 0.01) of calcitriol were significantly suppressed in normal rats following urine infusion when compared to saline infused rats (MCR, 0.30 +/- 0.01; PR, 32.9 +/- 4.1, N = 6). Different levels of protein intake by rats with renal failure produced by subtotal nephrectomy also alter the PR but not the MCR of calcitriol. Thus, the synthesis of calcitriol was significantly lower in rats with renal failure fed a high protein (50% protein) diet (17.6 +/- 0.7 ng/kg/day, N = 8, P less than 0.001) than in rats with renal failure fed a normal protein (20% protein) diet (22.2 +/- 1.4, N = 7). Thyroparathyroidectomy (TPTX) did not alter the MCR of calcitriol in renal failure, even though parathyroid hormone, which may suppress the degradation enzyme, could be elevated in this model of renal failure. The MCR of TPTXed rats with renal failure (0.15 +/- 0.01 ml/min/kg, N = 7) remained lower than that of the TPTXed control rats (0.19 +/- 0.01, N = 7, P less than 0.001), and chronic infusion of PTH to TPTXed rats with renal failure did not change the MCR of calcitriol (0.15 +/- 0.01, vs. control, 0.24 +/- 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Factors related to erythropoietin hypo-responsiveness in patients on chronic peritoneal dialysis

Background The present study was aimed at investigating the factors related to hypo-responsiveness to erythropoietin in patients on chronic peritoneal dialysis (PD). Methods We studied 44 patients with end-stage renal disease who had been on PD for more than 6 months and on erythropoietin (EPO) ≥6,000 U/week for more than 3 months. We expressed EPO resistance index (ERI) as weekly EPO dose per hematocrit (Hct) per body weight. The dose of EPO was titrated to maintain a target Hct level between 33% and 36%. Patients were divided into two groups according to weekly EPO dose. We compared the various factors in those two groups and, by using correlation and linear regression analysis, investigated factors that might predict EPO resistance. Results There were 13 patients in the EPO <150 U/kg per week group and 31 patients in the EPO ≥150 U/kg per week group. Among those 31 patients, there were five patients on EPO ≥300 U/kg per week. Compared to the EPO <150 U/kg per week group, the EPO ≥150 U/kg per week group had a lower normalized protein catabolic rate (nPCR), lower level of serum albumin and higher C-reactive protein (CRP). Correlation analysis showed that the ERI had a statistically significant correlation with CRP (r = 0.303, P < 0.05), serum albumin (r = −0.26, P < 0.05), parathyroid hormone (PTH) (r = −0.307, P < 0.05) and nPCR (r = −0.259, P < 0.05). These results show that CRP, serum albumin, PTH and nPCR are factors related to hypo-responsiveness. Multiple stepwise linear regression analysis showed that CRP was the most important independent predictor of EPO hypo-responsiveness. Conclusion CRP, serum albumin, nPCR and PTH are factors related to hypo-responsiveness. Inflammation contributes significantly to EPO hypo-responsiveness.     

The effect of i.v. iron alone or in combination with low-dose erythropoietin in the rapid correction of anemia of chronic renal failure in the predialysis period

BACKGROUND: It is now more and more evident that anemia of predialysis chronic renal failure (CRF) should be actively treated, since long-standing anemia may cause irremediable damage to the heart. The most common form of treatment of this anemia is subcutaneous erythropoietin (EPO). iron (Fe) deficiency can also contribute to anemia in predialysis CRF, and intravenous iron (i.v. Fe) can frequently improve it. It is possible, therefore, that the combination of EPO and i.v. Fe may have an additive effect, and cause a rapid improvement in anemia with relatively small doses of EPO. PURPOSE: The purpose of this study was an initial study: to assess the ability of a combination of low-dose EPO and i.v. Fe, given weekly for 5 doses, to correct the anemia of predialysis CRF patients compared to the use of i.v. Fe alone in a randomized study. In the follow-up study: to assess the ability of the maintenance of adequate iron stores for one year to achieve and maintain the target Hct of 35% with the minimum dose of EPO. Initial study: METHOD: Ninety predialysis CRF patients (creatinine clearance 10-40 ml/min/1.73 m2 received either: Group A (45 patients): 200 mg i.v. Fe as Fe sucrose (Venofer, Vifor Int.) once per week for 5 doses in combination with 2,000 international units (IU) EPO (Eprex, Cilag-Janssen), subcutaneously given simultaneously also for 5 doses. Group B (45 patients): the same dose of i.v. Fe as in Group A but without EPO. RESULTS: The mean increase in hematocrit (Hct) and hemoglobin (Hb) by one week after the last dose was greater in group A, 4.54 +/- 2.64% (p < 0.01) and 1.37 +/- 0.84 g% (p < 0.01), respectively, than in Group B, 2.74 +/- 2.72% (p < 0.05) and 0.91 +/- 0.78 g% (p < 0.05), respectively. 80% of those in Group A had an increase in Hct of 3 vol% or more compared to 48.9% in Group B (p < 0.01). 40% of those in Group A reached the target Hct of 35% compared to 28.9% in Group B (p > 0.05). Follow-up study: During a 12-month follow-up period, enough i.v. iron was given to maintain the Hct at 35%, while keeping the serum ferritin at < 400 ug/l and % Fe Sat at < 40%. If the i.v. Fe alone was not capable of maintaining the target Hct, EPO was given in increasing doses. Eighteen patients required dialysis. Of the 72 patients who did not require dialysis, 24 (33.3%) maintained the target Hct with i.v. Fe alone, without EPO. All the remaining 48 patients (66.7%) continued to receive EPO in addition to the i.v. Fe, and 47 achieved and maintained the target Hct with a mean EPO dose of 2,979 +/- 1,326 IU/week. CONCLUSION: The combination of low-dose EPO and i.v. Fe had a rapid and additive effect on the correction of anemia in CRF predialysis patients. Maintaining adequate iron stores with i.v. Fe during a subsequent maintenance phase allowed the target Hct of 35% to be reached and maintained with low-dose EPO in two-thirds of the predialysis patients and with no EPO at all in one-third.     

Effectiveness of erythropoiesis on supervised intradialytic oral iron and vitamin C therapy is correlated with Kt/V and patient weight

BACKGROUND: Poor compliance to oral medication and diet is common in hemodialysis (HD) patients and limits the ability of oral iron therapy to support erythropoiesis. Intravenous (i.v.) iron may be associated with undesirable and sometimes life-threatening complications. PATIENTS AND METHODS: We hypothesized that intradialytic oral iron therapy can overcome compliance problems and support effective maintenance erythropoiesis, which will keep Hct in the range of 33% to 36% and EPO requirements up to 50 units/week/kg. In a prospective observational study, SC EPO-treated hospital-based HD patients without conditions known to cause EPO resistance, were managed on intradialytic oral administration of iron and vitamin C. The primary endpoints were EPO requirements and resistance to EPO which standardized EPO requirements by the Hct level. Secondary endpoints included parameters that might affect the primary endpoints. Exclusion criteria were refusal to take oral medication, prestudy Hct < 27%, recent i.v. iron therapy or transfusions, bleeding, clinical conditions obligating Hct > 30% and known causes of EPO resistance. Twelve patients completed minimal follow-up period of 9 months. RESULTS: Mean Hct was 34.4% (range: 31.8% - 40.2%). EPO requirements were 61.7 +/- 28.2 units/kg and below 52.5 units/kg in 50% of patients. Patients were classified into equal groups according to resistance to EPO, which was positively correlated (r = 0.71 p < 0.01) with body weight and Kt/V (r = -0.38, p < 0.05). CONCLUSION: In conclusion, intradialytic oral iron therapy can support effective maintenance erythropoiesis in 50% of patients without known causes for EPO resistance. High response to EPO and low EPO requirement are correlated with lower body weight and possibly improved dialysis.     

Amelioration of postischaemic acute renal failure in conscious dogs by human atrial natriuretic peptide

We studied the effect of human ANP (alpha-hANP)-99-126 on the course of postischaemic acute renal failure in unilaterally nephrectomised, conscious dogs subjected to 120 min of renal ischaemia. In contrast to a control group A (n = 7), the investigational group B (n = 9) received an intra-aortic bolus injection of 100 micrograms/kg alpha-hANP and an additional continuous infusion of 0.3 micrograms/kg per min x 180 min immediately after ischaemia. On days 1 and 2 after ischaemia, only the bolus injection was repeated. Administration of hANP resulted in a marked restoration of GFR (29 +/- 2 vs 18 +/- 4 ml/min, P less than or equal to 0.01), diuresis (0.8 +/- 0.1 vs 0.5 +/- 0.1 ml/min, P less than or equal to 0.05), and natriuresis (44 +/- 7 vs 25 +/- 4 mumol/min, P less than or equal to 0.05) on the first postischaemic day, which was mirrored by a reduction in nitrogen retention (Purea: 8 +/- 1 vs 12 +/- 2 mmol/l P less than or equal to 0.05, Pcrea: 137 +/- 20 vs 204 +/- 37 mumol/l). Renal perfusion, however, was only slightly improved on day 1 after ischaemia (198 +/- 20 vs 163 +/- 27 ml/min, N.S.). Our data clearly demonstrate that repeated bolus applications of hANP ameliorate postischaemic acute renal failure in conscious dogs. We assume that the observed beneficial effect on GFR might be the consequence of an increase in glomerular capillary pressure rather than an improvement of renal perfusion.(ABSTRACT TRUNCATED AT 250 WORDS)