Brian J.G. Pereira

Urinary N-Acetyl-β-(D)-Glucosaminidase Activity and Kidney Injury Molecule-1 Level Are Associated with Adverse Outcomes in Acute Renal Failure

The role of urinary biomarkers of kidney injury in the prediction of adverse clinical outcomes in acute renal failure (ARF) has not been well described. The relationship between urinary N-acetyl-beta-(D)-glucosaminidase activity (NAG) and kidney injury molecule-1 (KIM-1) level and adverse clinical outcomes was evaluated prospectively in a cohort of 201 hospitalized patients with ARF. NAG was measured by spectrophotometry, and KIM-1 was measured by a microsphere-based Luminex technology. Mean Acute Physiology, Age, Chronic Health Evaluation II (APACHE II) score was 16, 43% had sepsis, 39% required dialysis, and hospital mortality was 24%. Urinary NAG and KIM-1 increased in tandem with APACHE II and Multiple Organ Failure scores. Compared with patients in the lowest quartile of NAG, the second, third, and fourth quartile groups had 3.0-fold (95% confidence interval [CI] 1.3 to 7.2), 3.7-fold (95% CI 1.6 to 8.8), and 9.1-fold (95% CI 3.7 to 22.7) higher odds, respectively, for dialysis requirement or hospital death (P < 0.001). This association persisted after adjustment for APACHE II, Multiple Organ Failure score, or the combined covariates cirrhosis, sepsis, oliguria, and mechanical ventilation. Compared with patients in the lowest quartile of KIM-1, the second, third, and fourth quartile groups had 1.4-fold (95% CI 0.6 to 3.0), 1.4-fold (95% CI 0.6 to 3.0), and 3.2-fold (95% CI 1.4 to 7.4) higher odds, respectively, for dialysis requirement or hospital death (P = 0.034). NAG or KIM-1 in combination with the covariates cirrhosis, sepsis, oliguria, and mechanical ventilation yielded an area under the receiver operator characteristic curve of 0.78 (95% CI 0.71 to 0.84) in predicting the composite outcome. Urinary markers of kidney injury such as NAG and KIM-1 can predict adverse clinical outcomes in patients with ARF.

Epidemiology and Outcomes of Acute Renal Failure in Hospitalized Patients: A National Survey

The aim of this study was to provide a broad characterization of the epidemiology of acute renal failure (ARF) in the United States using national administrative data and describe its impact on hospital length of stay (LOS), patient disposition, and adverse outcomes. Using the 2001 National Hospital Discharge Survey, a nationally representative sample of discharges from nonfederal acute care hospitals in the United States, new cases of ARF were obtained from hospital discharge records coded according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Multivariate regression analyses were used to explore the relation of ARF to hospital LOS and mortality as well as discharge disposition. Review of discharge data on a projected total of 29,039,599 hospitalizations identified 558,032 cases of ARF, with a frequency of 19.2 per 1000 hospitalizations. ARF was more commonly coded for in older patients; men; black individuals; and the setting of chronic kidney disease, congestive heart failure, chronic lung disease, sepsis, and cardiac surgery. ARF was associated with an adjusted prolongation of hospital LOS by 2 d (P < 0.001) and an adjusted odds ratio of 4.1 for hospital mortality and of 2.0 for discharge to short- or long-term care facilities. In a US representative sample of hospitalized patients, the presence of an ICD-9-CM code for ARF in discharge records is associated with prolonged LOS, increased mortality, and, among survivors, a greater requirement for posthospitalization care. These findings suggest that in the United States, ARF is associated with increased in-hospital and post-hospitalization resource utilization.

Transmission of Hepatitis C Virus by Organ Transplantation

BACKGROUND Liver disease is a frequent and major complication after organ transplantation. We sought to determine whether hepatitis C virus (HCV) is transmitted by organ transplantation and whether it causes post-transplantation liver disease. METHODS Serum samples from all cadaver organ donors to the New England Organ Bank between 1986 and 1990 were screened retrospectively for antibodies to HCV (anti-HCV) by enzyme-linked immunosorbent assay (ELISA). We reviewed the hospital records of all recipients of organs from anti-HCV-positive donors for evidence of liver disease. Serum samples from recipients obtained before transplantation and during follow-up were analyzed for anti-HCV. RESULTS Of 716 organ donors, 13 (1.8 percent) were positive for anti-HCV. Their organs (19 kidneys, 6 hearts, and 4 livers) went to 29 recipients. Non-A, non-B hepatitis developed after transplantation in 14 of the 29 (48 percent), for a prevalence 7.4 times the 6.5 percent prevalence after transplantation from untested donors that was previously reported by two institutions in the organ bank (P less than 0.0001). The liver disease began a mean of 3.8 months after transplantation and became chronic in 12 patients; the other 2 had subfulminant hepatic failure. Liver disease was more frequent in the patients who had received antilymphocyte preparations (P = 0.04). HCV was the cause of the post-transplantation liver disease in 12 of the 13 recipients (92 percent) for whom serum samples were available. Anti-HCV was detected by ELISA in eight and enzyme immunoassay in one; in three others, HCV RNA was detected by polymerase chain reaction in serum samples obtained after transplantation. CONCLUSIONS Organ transplantation can transmit hepatitis C. This raises serious questions about the continued acceptance of organs from donors positive for anti-HCV.

Ferumoxytol for Treating Iron Deficiency Anemia in CKD

Iron deficiency is an important cause of anemia in patients with chronic kidney disease (CKD), but intravenous iron is infrequently used among patients who are not on dialysis. Ferumoxytol is a novel intravenous iron product that can be administered as a rapid injection. This Phase III trial randomly assigned 304 patients with CKD in a 3:1 ratio to two 510-mg doses of intravenous ferumoxytol within 5 +/- 3 d or 200 mg of elemental oral iron daily for 21 d. The increase in hemoglobin at day 35, the primary efficacy end point, was 0.82 +/- 1.24 g/dl with ferumoxytol and 0.16 +/- 1.02 g/dl with oral iron (P < 0.0001). Among patients who were not receiving erythropoiesis-stimulating agents, hemoglobin increased 0.62 +/- 1.02 g/dl with ferumoxytol and 0.13 +/- 0.93 g/dl with oral iron. Among patients who were receiving erythropoiesis-stimulating agents, hemoglobin increased 1.16 +/- 1.49 g/dl with ferumoxytol and 0.19 +/- 1.14 g/dl with oral iron. Treatment-related adverse events occurred in 10.6% of patients who were treated with ferumoxytol and 24.0% of those who were treated with oral iron; none was serious. In summary, a regimen of two doses of 510 mg of intravenous ferumoxytol administered rapidly within 5 +/- 3 d was well tolerated and had the intended therapeutic effect. This regimen may offer a new, efficient option to treat iron deficiency anemia in patients with CKD.

Anemia: A Continuing Problem Following Kidney Transplantation

Cardiovascular disease is a leading cause of death among kidney transplant recipients. Anemia, a risk factor for cardiovascular complications among patients with chronic kidney disease, has not been well characterized in kidney transplant recipients. We performed a retrospective cohort study of the prevalence of and factors associated with anemia among 240 patients who underwent kidney transplantation at our institution. The mean hematocrit (Hct) rose from 33% at 1 month after transplantation to 40% at 12 months after transplantation. The proportion of patients with Hct < 36% was 76% at transplantation and 21% and 36%, 1 year and 4 years after transplantation, respectively. Six months after transplantation, women had higher likelihood (OR = 3.61) of Hct < 36%, while higher Hct at 3 months (OR = 0.67 for 1% higher Hct) and diabetes (OR = 0.14) were associated with a lower likelihood of Hct < 36%. Similar associations were seen 12 months after transplantation. Even among patients with Hct < 30%, only 36% had iron studies, 46% received iron supplementation and 40% received recombinant human erythropoietin. Awareness of factors associated with a lower Hct may prompt better anemia screening and management, potentially improving cardiovascular outcomes among kidney transplant recipients.

Ferumoxytol as an Intravenous Iron Replacement Therapy in Hemodialysis Patients

BACKGROUND AND OBJECTIVES Intravenous iron is a key component of anemia management for chronic kidney disease (CKD). Ferumoxytol is a unique intravenous iron product that can be administered as a rapid injection in doses up to 510 mg. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a randomized, open-label, controlled, multicenter Phase 3 trial to evaluate the safety and efficacy of intravenous ferumoxytol compared with oral iron. Anemic patients with CKD stage 5D on hemodialysis and on a stable erythropoiesis-stimulating agent regimen received either two injections of 510 mg of ferumoxytol within 7 d (n = 114) or 200 mg elemental oral iron daily for 21 d (n = 116). The primary efficacy endpoint was the change in hemoglobin from baseline to day 35. Safety was closely monitored. RESULTS Ferumoxytol resulted in a mean increase in hemoglobin of 1.02 +/- 1.13 g/dl at day 35 compared with 0.46 +/- 1.06 g/dl with oral iron (P = 0.0002). Twice as many ferumoxytol-treated patients than oral iron-treated patients achieved a > or =1 g/dl hemoglobin increase at day 35 (P = 0.0002). There was a greater mean increase in transferrin saturation (TSAT) with ferumoxytol compared with oral iron at day 35 (P < 0.0001). The larger hemoglobin increase after ferumoxytol compared with oral iron at day 35 persisted after adjustment for baseline hemoglobin, TSAT, and serum ferritin. Overall adverse event rates were comparable between groups. CONCLUSIONS In patients on hemodialysis, rapid intravenous injection of 510 mg of ferumoxytol led to significantly greater hemoglobin increases compared with oral iron, with comparable tolerability.

NADPH Oxidase p22phox and Catalase Gene Variants Are Associated with Biomarkers of Oxidative Stress and Adverse Outcomes in Acute Renal Failure

Reactive oxygen species are important mediators of injury in acute renal failure (ARF). Although polymorphisms that affect key pro- and antioxidant enzymes might alter the susceptibility to oxidative stress-mediated injury, the use of genetic epidemiology for the study of oxidative stress-related genes has received little attention in ARF. The relationship of single-nucleotide polymorphisms in the coding region (C to T substitution at position +242) of the pro-oxidant enzyme NADPH oxidase p22phox subunit gene and in the promoter region (C to T substitution at position -262) of the antioxidant enzyme catalase gene to adverse clinical outcomes was evaluated prospectively in a cohort of 200 hospitalized patients with established ARF of mixed cause and severity. Genomic DNA was extracted from peripheral blood leukocytes and analyzed with a restriction fragment length polymorphism PCR method. Genotype-phenotype associations were characterized by measuring circulating nitrotyrosine and catalase activity. Observed and expected genotype frequencies were not significantly different, and overall baseline characteristics were not significantly different according to the various genotype groups. A genotype-phenotype association was demonstrable between the NADPH oxidase p22phox genotypes and plasma nitrotyrosine level (P = 0.06), as well as between the catalase genotypes and whole-blood catalase activity (P < 0.001). Compared with the NADPH oxidase p22phox CC genotype group, the T-allele group had a higher cumulative probability of remaining hospitalized (P = 0.03). Compared with the NADPH oxidase p22phox CC genotype, the T-allele carrier state was associated with 2.1-fold higher odds for dialysis requirement or hospital death (P = 0.01). This association persisted with 2.0- to 2.2-fold higher odds for this composite outcome after adjustment for race; gender; age; and the Acute Physiology and Chronic Health Evaluation II score (P = 0.03), the Multiple Organ Failure score (P = 0.01), or presence of sepsis (P = 0.02). The polymorphism in the gene that encodes the NADPH oxidase p22phox subunit at position +242 is associated with dialysis requirement or hospital death among patients with ARF. Larger studies are needed to confirm these relationships.

A controlled study of hepatitis C transmission by organ transplantation

Hepatitis C virus (HCV) can be transmitted by transplantation of cadaver organs from donors with antibody to HCV (anti-HCV); therefore, transplantation of organs from anti-HCV positive donors to anti-HCV-negative recipients has been discouraged. We have looked at outcomes in recipients of organs from anti-HCV positive and negative donors to determine whether this advice is well-founded. Stored sera from 716 consecutive cadaver organ donors procured by the New England Organ Bank between 1986 and 1990 were tested for anti-HCV by a first-generation ELISA (ELISA1); 13 (1.8%) were positive. 29 recipients who received organs from these donors were the study group. 37 donors were randomly selected from 703 ELISA1-negative cadaver organ donors. 74 recipients of organs from these 37 donors were the control group. Clinical records were reviewed and recipient sera were tested for anti-HCV with a second-generation ELISA (ELISA2), and HCV RNA was tested for by polymerase chain reaction. Median post-transplant follow-up was 42 and 49 months for study and control groups. Post-transplantation prevalence of anti-HCV and HCV RNA was 67% and 96% among recipients from anti-HCV-positive donors, and 20% and 18% among recipients from anti-HCV-negative donors (p < 0.001). Post-transplantation non-A, non-B hepatitis, graft loss, and death were observed in 55%, 52%, and 31% among recipients of organs from anti-HCV-positive donors, and 16%, 53%, and 33% among recipients from anti-HCV-negative donors. In a proportional hazards model, the relative risks for non-A, non-B hepatitis, graft loss, and death among recipients from anti-HCV-positive donors were 4.37 (95% CI 1.97-9.70), 0.93 (0.51-1.70), and 0.89 (0.41-1.93). Transmission of HCV infection by organ transplantation increased the risk of liver disease among recipients. However, after 3.5 years, donor HCV infection did not adversely affect patient survival or graft survival.

Impact of dialysis room and reuse strategies on the incidence of hepatitis C virus infection in haemodialysis units

BACKGROUND Despite the advent of screening of blood products for anti-hepatitis C virus (HCV), the incidence of HCV infection among haemodialysis (HD) patients is alarmingly high and suggest transmission within the HD unit. To analyse trends in the prevalence and incidence of HCV infection, and evaluate the impact of dialysis room and reuse policies on the incidence of HCV infection, a hospital survey instrument was sent out to medical directors of all 71 HD units in Portugal in August 1994. Information for the years 1991, 1992 and 1993 was requested with respect to HCV infection, defined as positive anti-HCV test. Sixty-two of 71 units (87%) treating 4232 patients in 1993 responded. Overall, data from 5774 patient-years were available for analyses. Observations over multiple intervals were pooled into a single sample, and pooled logistic regression was used to evaluate the relationship between risk factors/strategies and incidence of HCV infection. By 1993, regular anti-HCV testing of patients and staff was practised by 98% and 82% of units, respectively. There was a significant decline in the incidence of HCV infection from 9.9% in 1991 to 5.7% in 1992 and 5.1% in 1993. The incidence was directly related to the prevalence in the dialysis unit. Units with a prevalence of less than 19% had an annual incidence of 2.5% compared to a 35.3% incidence in units with a prevalence greater than 60%. There was wide variation in the incidence of HCV infection in HD units across the country, with geographical location, unit ownership and socioeconomic factors playing a significant role. The incidence was lowest among units that: (i) were located in the northern regions of the country; (ii) were private hospital-based units; and (iii) used dedicated machines or separate rooms for anti-HCV-positive patients. The incidence among units that reprocessed dialysers (6.1%) was not significantly different from that among units that did not reprocess dialysers (7.4%). However, among units that did reprocess dialysers, the incidence of HCV infection was lowest in: (i) units that used separate rooms for reprocessing dialysers from anti-HCV-positive patients or did not reprocess these dialysers; and (ii) units that used Renalin as the sterilant. These results suggest the transmission of HCV infection in HD units and that use of dedicated machines and isolation of anti-HCV-positive patients and their dialysers may reduce the incidence of HCV infection.

Physicochemical properties of ferumoxytol, a new intravenous iron preparation

Background  Intravenous iron is a critical component of anaemia management. However, currently available preparations have been associated with the release of free iron, a promoter of bacterial growth and oxidative stress.