Exacerbation of radiocontrast nephrotoxicity by endothelin receptor antagonism.

BACKGROUND: Endothelin is a potent vasoconstrictor that has been implicated in the pathogenesis of radiocontrast nephrotoxicity. Endothelin antagonists may reduce the renal hemodynamic abnormalities following radiocontrast administration. METHODS: One hundred fifty-eight patients with chronic renal insufficiency [mean serum creatinine +/- SD = 2.7 +/- 1.0 mg/dL (242. 3 to +/- 92.8 micromol/L)] and undergoing cardiac angiography were randomized to receive either a mixed endothelin A and B receptor antagonist, SB 290670, or placebo. All patients received intravenous hydration with 0.45% saline before and after radiocontrast administration. Serum creatinine concentrations were measured at baseline, 24 hours, 48 hours, and 3 to 5 days after radiocontrast administration. The primary end point was the mean change in serum creatinine concentration from baseline at 48 hours; the secondary end point was the incidence of radiocontrast nephrotoxicity, defined as an increase in serum creatinine of > or =0.5 mg/dL (44 micromol/L) or > or = 25% from baseline within 48 hours of radiocontrast administration. RESULTS: The mean increase in serum creatinine 48 hours after angiography was higher in the SB 209670 group [0.7 +/- 0. 7 mg/dL (63.5 +/- 58.6 micromol/L)] than in the placebo group [0.4 +/- 0.6 mg/dL (33.6 +/- 55.1 micromol/L), P = 0.002]. The incidence of radiocontrast nephrotoxicity was also higher in the SB 209670 group (56%) compared with placebo (29%, P = 0.002). This negative effect of SB 209670 was apparent in both diabetic and nondiabetic patients. Adverse effects, especially hypotension or decreased blood pressure, were more common in the SB 209670 group. CONCLUSIONS: In patients with chronic renal insufficiency who were undergoing cardiac angiography, endothelin receptor antagonism with SB 209670 and intravenous hydration exacerbate radiocontrast nephrotoxicity compared with hydration alone.

Effects of normal hematocrit on ambulatory blood pressure in epoetin-treated hemodialysis patients with cardiac disease.

BACKGROUND: Hypertension is a recognized complication of partial correction of anemia with recombinant human erythropoietin (epoetin) in hemodialysis patients. We used interdialytic ambulatory blood pressure (ABP) monitoring to study the effects of partially corrected anemia versus normal hematocrit (hct) on BP in hemodialysis patients. METHODS: Repeated interdialytic ABP monitoring was performed for up to one year in 28 chronic hemodialysis patients with cardiac disease who were randomized to achieve and maintain normal hct levels (42 +/- 3%, group A) or anemic hct levels (30 +/- 3%, group B) with epoetin. Routine BP measurements obtained at dialysis treatments were also evaluated. RESULTS: Mean hct levels were 30.7 +/- 0.7% in group A and 30.6 +/- 0.7% in group B at baseline, then 39.3 +/- 1.2% (group A) and 33.5 +/- 0.6% (group B) at four months, and 42.0 +/- 1.1% (group A) and 30.4 +/- 1.0% (group B) at 12 months. Baseline ABP and routine dialysis unit BP levels were not different between the groups. At 2, 4, 8, and 12 months of follow-up, there were no statistically significant differences in any BP parameters between groups or increases in any BP parameters in either group A or group B patients compared with baseline. At 12 months, the mean nighttime diastolic BP (DBP) in group A patients was slightly but significantly lower than the mean daytime DBP (daytime DBP 76.6 +/- 1.9 mm Hg vs. nighttime DBP 72.9 +/- 2.1 mm Hg, P < 0.05). The mean daytime and nighttime BPs were not different from each other at two, four, and eight months in group A or at any time in group B, and in both groups, most patients had little diurnal change in BP. CONCLUSION: Correction of hct to normal with epoetin in chronic hemodialysis patients with cardiac disease did not cause increased BP as assessed by interdialytic ABP monitoring or by the measurement of routine predialysis and postdialysis BP. There was little diurnal change in systolic or diastolic BP at baseline or after correction of anemia to normal levels, and although mean nighttime DBP was lower than mean daytime DBP at 12 months in group A, the maintenance of normal hct levels did not affect the abnormal diurnal BP pattern seen at moderately anemic hct levels in most patients.

Bromfenac disposition in patients with impaired kidney function.

OBJECTIVES: To compare the pharmacokinetics of bromfenac among normal subjects and renally compromised patients and patients with end-stage renal disease. METHODS: Bromfenac pharmacokinetics were examined after a single 50 mg oral dose in 18 subjects with normal kidney function, 12 subjects with decreased kidney function, and 10 dialysis-dependent subjects. Protein binding was assessed by equilibrium dialysis. RESULTS: Mean peak concentrations and areas under the concentration versus time curve ranged from 3.3 to 3.9 micrograms/ml and 5.1 to 6.9 micrograms.hr/ml, respectively. The mean unbound fraction in the subjects receiving dialysis (0.29%) was nearly twice that in the subjects with normal kidney function (0.17%) and in the subjects with impaired kidney function (0.16%), but no differences were detected in clearance, volume of distribution, or their free fraction-corrected counterparts. Bromfenac half-life nearly doubled in the impaired and dialysis groups but was shorter than the anticipated 8-hour dose interval. Eight subjects had a total of 11 study events; none were serious and all were self-limited. CONCLUSIONS: These findings suggest that no dosage adjustment is necessary in patients with impaired kidney function, but clinical monitoring appropriate for their individual condition is recommended.

Contrast media-associated nephrotoxicity.

Contrast media-associated nephrotoxicity (CM-AN) continues to be a common cause of hospital-acquired acute renal failure. This review of CM-AN discusses the pathogenesis, clinical features, incidence, risk factors with an emphasis on pre-existing renal insufficiency and diabetes mellitus, volume of contrast media, low osmolar versus high osmolar contrast media, and prophylaxis. Although the literature contains an abundance of information concerning CM-AN, areas of uncertainty remain in respect to clinical significance, risk with modem day radiological techniques and contrast media, optimal prophylactic regimens, and criteria for creatinine screening before contrast media administration.

Contrast media-associated nephrotoxicity.

Contrast media-associated nephrotoxicity continues to be a common cause of acute renal failure. We review recent developments in our understanding of the pathogenesis of this complication, focusing on the role of vasoactive substances which include adenosine, endothelium-derived relaxing factor, and endothelin. An overview of clinical features is presented with an emphasis on the value of low osmolar contrast media in azotemic patients. Prophylactic strategies are reviewed focusing on saline hydration alone, vasoactive pharmacological agents, theophylline, 'prophylactic hemodialysis', and possible differences in how these maneuvers affect diabetic and non-diabetic azotemic patients are discussed.

Severe, irreversible renal failure after ifosfamide treatment. A clinicopathologic report of two patients.

BACKGROUND: Chronic renal failure has been described only rarely in patients treated with the alkylating agent ifosfamide, which is known to cause renal tubular dysfunction and acute renal failure, and the associated histopathologic features have not been well characterized. METHODS: This report describes the clinical course and renal histopathologic features in two patients in whom irreversible renal failure occurred requiring permanent dialysis after treatment with ifosfamide. RESULTS: Irreversible renal failure developed in a 60-year-old man with malignant fibrohistiocytoma, requiring chronic dialysis within several months after he received two cycles of ifosfamide in a cumulative dose of 28 g/m2. The second patient, a 53-year-old man with osteogenic sarcoma, received two cycles of ifosfamide with a cumulative dose of 26 g/m2, after initial therapy with cisplatin and doxorubicin. His renal function worsened over the next 11 months, at which time permanent dialysis was initiated. In neither patient were other causes of renal failure apparent. Renal biopsies in both patients showed diffuse tubular epithelial damage with degenerative and regenerative epithelial changes, diffuse interstitial fibrosis, and arterial and arteriolar sclerosis. CONCLUSIONS: Irreversible severe renal failure, which appears due to nephrotoxic damage of renal tubular epithelium and/or the renal microvasculature may develop after treatment with ifosfamide. Neither large cumulative doses of ifosfamide nor prior cisplatin treatment are necessary for this toxicity to occur. Because a rising serum creatinine may develop months after completion of treatment with ifosfamide, renal function should be monitored closely both during and after ifosfamide treatment.

Health-related quality of life associated with recombinant human erythropoietin therapy for predialysis chronic renal disease patients.

The investigators evaluated the impact of recombinant human erythropoietin (r-HuEPO) therapy on health-related quality of life (HRQL) in predialysis chronic renal disease patients with anemia. Eighty-three patients were entered into a randomized, parallel-group, open-label clinical trial with follow-up evaluations over 48 weeks. Forty-three patients were assigned to r-HuEPO treatment, and 40 patients were assigned to an untreated control group. Hematocrit levels were measured at baseline and monthly. HRQL was assessed at baseline and at weeks 16, 32, and 48. The HRQL assessment included measures of physical function, energy, role function, health distress, cognitive function, social function, home management, sexual dysfunction, depression, and life satisfaction. Significant improvements in hematocrit levels were observed in the r-HuEPO-treated group (P < 0.0001), and no changes were seen in the untreated group. Correction of anemia (hematocrit > or = 36) occurred in 79% of r-HuEPO-treated patients and 0% of control patients. Significant improvements in assessments of energy (P < 0.05), physical function (P < 0.05), home management (P < 0.05), social activity (P < 0.05), and cognitive function (P < 0.05) were found for the r-HuEPO-treated group. No changes were observed in the control group, except for a decrease in physical function (P < 0.05). Between-group differences favoring the r-HuEPO-treated group were found for energy (P < 0.05) and physical functioning (P < 0.05). In patients receiving r-HuEPO, significant improvements were seen in hemotocrit levels, and these increases resulted in improvements in HRQL.

Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial. The Iohexol Cooperative Study.

The incidence of nephrotoxicity occurring with the nonionic contrast agent, iohexol, and the ionic contrast agent, meglumine/sodium diatrizoate, was compared in 1196 patients undergoing cardiac angiography in a prospective, randomized, double-blind multicenter trial. Patients were stratified into four groups: renal insufficiency (RI), diabetes mellitus (DM) both absent (N = 364); RI absent, DM present (N = 318); RI present, DM absent (N = 298); and RI and DM both present (N = 216). Serum creatinine levels were measured at -18 to 24, 0, and 24, 48, and 72 hours following contrast administration. Prophylactic hydration was administered pre- and post-angiography. Acute nephrotoxicity (increase in serum creatinine of > or = 1 mg/dl 48 to 72 hours post-contrast) was observed in 42 (7%) patients receiving diatrizoate compared to 19 (3%) patients receiving iohexol, P < 0.002. Differences in nephrotoxicity between the two contrast groups were confined to patients with RI alone or combined with DM. In a multivariate analysis, baseline serum creatinine, male gender, DM, volume of contrast agent, and RI were independently related to the risk of nephrotoxicity. Patients with RI receiving diatrizoate were 3.3 times as likely to develop acute nephrotoxicity compared to those receiving iohexol. Clinically severe adverse renal events were uncommon (N = 15) and did not differ in incidence between contrast groups (iohexol N = 6; diatrizoate N = 9). In conclusion, in patients undergoing cardiac angiography, only those with pre-existing RI alone or combined with DM are at higher risk for acute contrast nephrotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of recombinant human erythropoietin on renal function in chronic renal failure predialysis patients.

A study was undertaken to ascertain the effects of recombinant human erythropoietin (r-HuEPO) on renal function in chronic renal failure predialysis patients. The effect of improvement of anemia by r-HuEPO on the rate of decline in renal function in predialysis patients has not been previously studied prospectively in a large number of patients using reliable measures of glomerular filtration rate (GFR). To investigate the efficacy, safety, and impact of r-HuEPO therapy in chronic renal insufficiency patients, a 48-week, randomized, open-label, multicenter study was initiated in 83 anemic, predialysis (serum creatinine 3 to 8 mg/dL) patients. Serial GFRs were measured using 125I-iothalamate clearance. Forty patients were randomized to the untreated arm and 43 patients to the treatment arm (50 U/kg r-HuEPO subcutaneously three times weekly). Baseline characteristics were comparable for the r-HuEPO-treated and untreated groups. During this 48-week study, GFR, mean arterial blood pressure, and daily protein intake were not significantly different between the two groups. There was a statistically significant increase in hematocrit for the r-HuEPO-treated group that was not associated with acceleration of deterioration in residual renal function. This was demonstrated by the lack of a significant (P = 0.376) between-group difference in mean change in GFR from baseline to last available value for the r-HuEPO-treated (-2.1 +/- 3.2 mL/min) and untreated (-2.8 +/- 3.5 mL/min) groups. This study concludes that r-HuEPO therapy improves anemia in predialysis patients and does not accelerate the rate of progression to end-stage renal disease.

Nephrotoxic risks of renal angiography: contrast media-associated nephrotoxicity and atheroembolism--a critical review.

Renal angiography remains the "gold standard" procedure for the detection of renal artery stenosis. However, clinicians often avoid renal angiography because of fears of contrast media-associated nephrotoxicity (CM-AN) and atheroembolism. This review focuses on these potential angiographic complications, with particular emphasis, in the case of CM-AN, on clinical features, incidence, risk factors with an emphasis on pre-existing renal insufficiency and diabetes mellitus, volume of contrast media, low osmolar versus high osmolar contrast media, and prophylaxis. For atheroembolism, areas emphasized are pathology, clinical features, precipitating features, and incidence in various settings. Although the literature contains an abundance of information about CM-AN and atheroembolism, this review identified multiple areas of uncertainty regarding features of both of these complications. For example, additional studies are needed to determine the incidence of CM-AN, both asymptomatic and clinically severe, in patients with a wide range of pre-existing renal insufficiency with and without diabetes mellitus, following low volume digital subtraction renal angiography with low osmolar contrast media. In a similar manner, studies are needed with adequate postcontrast observation periods to determine the true incidence of clinically significant atheroembolism following diagnostic renal angiography and angioplasty and techniques that may modify this complication. Until further knowledge in both of these areas is available, it is difficult to precisely determine the risks of renal angiography and/or angioplasty in the azotemic patient suspected of or having renal ischemic disease using modern radiologic techniques.

Low-osmolality contrast media and the risk of contrast-associated nephrotoxicity.

OBJECTIVES: The authors review clinical data, including those from the recent Iohexol Cooperative Group trial, regarding the nephrotoxic potential of low-osmolar versus high-osmolar contrast media. The clinical characteristics and postulated mechanisms of contrast-associated nephrotoxicity are also considered. METHODS: The principal strategy for identifying relevant articles was to search the MEDLINE database using the MeSH heading "contrast media nephrotoxicity." Articles from 1966 through 1992 that were considered included original research papers as well as reviews. Those articles selected for detailed review documented original research pertaining to use of low-osmolar or high-osmolar agents. Selected abstracts for pertinent society meetings were also used. No attempt was made to be complete in describing the field. Rather, specific articles that selectively address the question of nephrotoxicity related to the osmolar content of contrast media were used for discussion. RESULTS AND CONCLUSIONS: In-vitro and animal studies indicate that renal changes possibly involved in the pathogenesis of contrast-associated nephrotoxicity seem to be ameliorated with low-osmolar contrast media, compared with high-osmolar agents. Several recent clinical trials, as well as a meta-analysis combining 24 randomized studies, suggest that the risk of contrast-associated nephrotoxicity is similarly low with high-osmolar and low-osmolar agents among otherwise stable patients with normal renal function, but that low-osmolar contrast is less nephrotoxic than media with high osmolality in patients with pre-existing renal insufficiency.

Multicenter trial of ionic versus nonionic contrast media for cardiac angiography. The Iohexol Cooperative Study.

Contrast agents used for cardiac angiography are different in regard to ionicity, osmolality and physiologic effects. The nonionic contrast media have been shown to have less toxic effects and a better safety profile than do higher osmolar agents. To better assess this risk, clinically stable patients undergoing cardiac angiography were stratified according to the presence of diabetes mellitus, and level of serum creatinine, and then randomized to receive either iohexol (Omnipaque 350) or sodium meglumine diatrizoate (Renografin 76). All adverse events that occurred during and immediately after angiography were tabulated. A multivariate model was used to identify patients at increased risk for adverse outcome. The 1,390 patients were randomized to iohexol (n = 696) or diatrizoate (n = 694). Significant differences were found in the number of patients with contrast media-related adverse (iohexol vs diatrizoate: 10.2 vs 31.6%; p < 0.001) and cardiac adverse (7.2 vs 24.5%; p < 0.001) events. Severe reactions and the need for treatment were more frequent with diatrizoate than with iohexol, but there was no difference in the incidence of death. The presence of New York Heart Association classification 3 or 4 and serum creatinine > or = 1.5 mg/dl predicted a higher incidence of adverse events as a result of contrast media alone. Use of iohexol is associated with a lower incidence of all types of adverse events during cardiac angiography than is diatrizoate.

A controlled trial of recombinant human erythropoietin and nandrolone decanoate in the treatment of anemia in patients on chronic hemodialysis.

We conducted a prospective, randomized study in chronic hemodialysis patients in order to determine whether the erythropoietic response to low dose recombinant human erythropoietin (rHuEpo) could be enhanced by administration with androgens. Patients received rHuEpo 40 U/kg intravenously three times weekly either alone (Group 1, n = 6) or with weekly intramuscular injection of 2 mg/kg nandrolone decanoate (Group 2, n = 6) for up to 16 weeks. Baseline hct, ferritin, N-terminal parathyroid hormone, and aluminum levels were similar. The mean weekly rate of rise in hct was 0.32 +/- 0.13% in Group 1 and 0.37 +/- 0.11% in Group 2, p = NS. Three of 6 patients in Group 1, but only 1 of 6 patients in Group 2, reached the target hct of 30% within 16 weeks. Two patients in Group 2 requested that the nandrolone decanoate be stopped prior to reaching target hct because of unacceptable side effects (acne). We conclude that many chronic hemodialysis patients appear to respond adequately to rHuEpo at the dose used in our study. Nandrolone decanoate does not enhance the response rate to this rHuEpo dose and is associated with significant side effects.

Hypoglycemia with hyperinsulinemia in a chronic hemodialysis patient following parathyroidectomy.

We report a chronic hemodialysis patient with severe hyperparathyroidism who developed hypoglycemia with inappropriate hyperinsulinemia following parathyroidectomy. An abrupt fall in parathyroid hormone level and administration of large amounts of calcitriol may have resulted in increased insulin release and enhanced tissue sensitivity to insulin producing sustained hypoglycemia in this patient.

Renal aspects of therapy for human immunodeficiency virus and associated opportunistic infections.

Patients with human immunodeficiency virus infection and the acquired immunodeficiency syndrome are often treated with a variety of potentially nephrotoxic drugs. This review summarizes the renal, fluid, and electrolyte complications of drugs used to treat human immunodeficiency virus and associated opportunistic infections. The pharmacokinetics of the drugs are also briefly reviewed, and dosing guidelines for the use of these drugs in patients who have renal insufficiency or who are receiving dialysis are provided.

Thrombotic microangiopathy and renal failure associated with antineoplastic chemotherapy.

Five patients with carcinoma developed thrombotic microangiopathy (characterized by renal insufficiency, microangiopathic hemolytic anemia, and usually thrombocytopenia) after treatment with cisplatin, bleomycin, and a vinca alkaloid. One patient had thrombotic thrombocytopenic purpura, three the hemolytic-uremic syndrome, and one an apparent forme fruste of one of these disorders. Histologic examination of the renal tissue showed evidence of intravascular coagulation, primarily affecting the small arteries, arterioles, and glomeruli. Because each patient was tumor-free or had only a small tumor at the onset of this syndrome, the thrombotic microangiopathy may have been induced by chemotherapy. Diagnosis of this potentially fatal complication may be delayed or missed if renal tissue or the peripheral blood smear is not examined, because renal failure may be ascribed to cisplatin nephrotoxicity and the anemia and thrombocytopenia to drug-induced bone marrow suppression.

Correction of drug binding defects in uremia in vitro by anion exchange resin treatment.

Serum protein binding of weakly acidic drugs is impaired in uremia, but that of basic drugs tends to be normal. Treatment of uremic serum with anion exchange resin (Amberlite CG-400, acetate form) corrected binding defects for three acidic drugs (nafcillin, salicylate and sulfamethoxazole) but did not affect the binding of two basic drugs (trimethoprim and quinidine). Resin treatment of normal human serum did not alter the binding of these five drugs. Extraction of the acetate buffer eluate from resin exposed to uremic serum with n-butyl chloride at acidic pH (3.0) resulted in a fraction that could induce similar binding defects in normal human serum. The factor(s) responsible for binding defects in uremia appears to be lipid soluble, weakly acidic, and dialyzable. It is believed to be tightly bound to albumin at physiologic pH, but dissociates from it at acidic pH. These findings further support the previously proposed hypothesis that drug-binding defects in uremia are due to accumulation of certain endogenous metabolic product(s).