Brendan J. Barrett

Contrast material-induced renal failure in patients with diabetes mellitus, renal insufficiency, or both. A prospective controlled study.

To determine the risk of nephrotoxicity induced by the infusion of radiographic contrast material, we undertook a prospective study of consecutive patients undergoing radiographic procedures with intravascular contrast material. There were three study groups: patients with diabetes mellitus and normal renal function (n = 85), patients with preexisting renal insufficiency (serum creatinine level, greater than or equal to 150 mumol per liter) without diabetes (n = 101), and patients with both diabetes and renal insufficiency (n = 34). The control group consisted of patients undergoing CT scanning or abdominal imaging procedures without the infusion of contrast material who had diabetes mellitus (n = 59), preexisting renal insufficiency (n = 145), or both (n = 64). Clinically important acute renal failure (defined as an increase of greater than 50 percent in the serum creatinine level) attributable to the contrast material did not occur in nondiabetic patients with preexisting renal insufficiency or in diabetics with normal renal function. The incidence of clinically important contrast-induced renal failure among the diabetic patients with preexisting renal insufficiency was 8.8 percent (95 percent confidence interval, 1.9 to 23.7 percent), as compared with 1.6 percent for the controls. The incidence of acute renal insufficiency, more broadly defined as an increase of greater than 25 percent in the serum creatinine level after the infusion of contrast material, was 11.8 percent among all patients with preexisting renal insufficiency. After the exclusion of patients whose acute renal insufficiency could be attributed to other causes, the incidence was 7.0 percent (95 percent confidence interval, 3.2 to 12.8 percent), as compared with 1.5 percent in the control group. The risk of acute renal insufficiency attributable to the contrast material was therefore 5.5 percent, and the relative risk associated with the infusion of contrast material was 4.7. These rates were similar whether the osmolarity of the contrast material was high or low. We conclude that there is little risk of clinically important nephrotoxicity attributable to contrast material for patients with diabetes and normal renal function or for nondiabetic patients with preexisting renal insufficiency. The risk for those with both diabetes and preexisting renal insufficiency is about 9 percent, which is lower than previously reported.

Left ventricular mass index increase in early renal disease: Impact of decline in hemoglobin

Cardiovascular disease occurs in patients with progressive renal disease both before and after the initiation of dialysis. Left ventricular hypertrophy (LVH) is an independent predictor of morbidity and mortality in dialysis populations and is common in the renal insufficiency population. LVH is associated with numerous modifiable risk factors, but little is known about LV growth (LVG) in mild-to-moderate renal insufficiency. This prospective multicenter Canadian cohort study identifies factors associated with LVG, measured using two-dimensional-targeted M-mode echocardiography. Eight centers enrolled 446 patients, 318 of whom had protocol-mandated clinical, laboratory, and echocardiographic measurements recorded. We report 246 patients with assessable echocardiograms at both baseline and 12 months with an overall prevalence of LVH of 36%. LV mass index (LVMI) increased significantly (>20% of baseline or >20 g/m2) from baseline to 12 months in 25% of the population. Other than baseline LVMI, no differences in baseline variables were noted between patients with and without LVG. However, there were significant differences in decline of Hgb level (-0.854 v -0.108 g/dL; P = 0.0001) and change in systolic blood pressure (+6.50 v -1.09 mm Hg; P = 0.03) between the groups with and without LVG. Multivariate analysis showed the independent contribution of decrease in Hgb level (odds ratio [OR], 1.32 for each 0.5-g/dL decrease; P = 0.004), increase in systolic blood pressure (OR, 1.11 for each 5-mm Hg increase; P = 0.01), and lower baseline LVMI (OR, 0.85 for each 10-g/m2; P = 0.011) in predicting LVG. Thus, after adjusting for baseline LVMI, Hgb level and systolic blood pressure remain independently important predictors of LVG. We defined the important modifiable risk factors. There remains a critical need to establish optimal therapeutic strategies and targets to improve clinical outcomes.

Guidelines for the management of chronic kidney disease

New guidelines for the management of chronic kidney disease have been developed by the Canadian Society of Nephrology (Appendix 1 contains the full-text guidelines; available at [www.cmaj.ca/cgi/content/full/179/11/1154/DC1][1]). These guidelines describe key aspects of the management of chronic

Plasma Exchange When Myeloma Presents as Acute Renal Failure: A Randomized, Controlled Trial

Context Does plasma exchange benefit patients with multiple myeloma and renal failure? Contribution This 6-month randomized trial involved 104 patients with acute renal failure at the onset of myeloma. A composite outcome of death, dialysis dependence, or severely reduced kidney function occurred in 57.9% of patients given 5 to 7 plasma exchanges and in 69.2% of patients given conventional therapy (difference, 11.3% [95% CI, 8.3% to 29.1%]). Cautions Although these findings suggest no substantial benefits of plasma exchange, the wide 95% CI around the difference between groups means that large benefit or some harm is possible. The Editors Of patients with newly diagnosed myeloma, 12% to 20% present with acute renal failure (1-3). After correction of hypovolemia and hypercalcemia, 77% to 100% of patients with renal insufficiency may have biopsy-proven cast nephropathy or interstitial inflammation (4-8). Renal inflammation results from excessive filtered monoclonal light chains, which are transported to the interstitium of the kidney via specific receptors in the proximal tubule. These receptors are overloaded by excess light chains, resulting in an overflow to the distal tubule where combination with TammHorsfall protein produces obstructive casts (9-13). Plasma exchange transiently removes light chains and, thus, may be beneficial in treating some patients with acute renal failure (14-19). Two small, randomized trials involving 29 and 21 participants, respectively, provide conflicting results (4, 19). Despite a lack of convincing evidence, recent reviews and management guidelines endorse plasma exchange as useful for preventing acute renal failure associated with myeloma kidney (15, 20-23). The uncertainty about the role of plasma exchange prompted us to conduct a multicenter randomized, controlled trial in patients with myeloma-associated acute kidney failure. The primary research question was whether 5 to 7 plasma exchanges, in addition to conventional therapy, at the onset of myeloma with acute renal failure reduced the composite outcome of death, dialysis dependence, or a glomerular filtration rate (GFR) less than 0.29 mLs2m2 (<30 mL/min per 1.73 m2) at 6 months. Methods Study Participants Study participants included patients with newly diagnosed multiple myeloma and progressive acute kidney failure. All had a bone marrow aspirate with more than 10% plasma cells and a monoclonal light chain in their urine, plasma, or renal tissue. We defined progressive acute kidney failure as a serum creatinine level greater than 200 mol/L (>2.3 mg/dL) with an increase greater than 50 mol/L (>0.6 mg/dL) in the preceding 2 weeks despite correction of hypercalcemia, hypovolemia, and metabolic acidosis in patients with normal-sized kidneys on renal ultrasonography. Exclusion criteria were age less than 18 years or greater than 81 years, obstruction on renal ultrasonography (required examination), use of intravenous contrast or nonsteroidal anti-inflammatory drugs during the previous 2 weeks, previous treatment for myeloma, pregnancy, or inability to provide informed consent. Research Design and Intervention Fourteen Canadian medical centers participated in the trial: 3 centers recruited more than 10 patients each, 5 centers recruited 5 to 9 patients each, and 6 centers recruited fewer than 5 patients each. Patients who fulfilled entry criteria were referred by their oncologist or nephrologist to the apheresis physician at their center. The apheresis physician explained the nature of the study by using a human ethicsapproved letter of information. We requested informed consent, and if we obtained it, we randomly assigned the participants centrally by telephone, by using a computer random-number generator (24, 25), to either receive or not to receive plasma exchange. We stratified randomization by 4 strata according to whether patients were receiving vincristineadriamycindexamethasone (VAD) and whether patients were receiving short-term hemodialysis. Recruiting physicians were unaware of the treatment allocation before study entry. Of note, randomization used 104 of the 1568 concealed random-numbergenerated allocations, and the imbalanced assignment of 61 patients to plasma exchange and 43 patients to control was solely due to random chance. After random blinded allocation, participants were treated in an unblinded manner. We enrolled participants from September 1998 to October 2003. The institutional ethics review boards of the 14 Canadian sites approved the protocol. Patients who were randomly assigned to receive plasma exchange underwent 5 to 7 plasma exchange procedures within the first 10 days of study entry, concurrent with the initiation of chemotherapy. They received a routine plasma exchange of 50 mL per kg of body weight with acid citrate dextrose as the anticoagulant through a Spectra cell separator (Gambro BCT, Lakewood, Colorado), using 5% human serum albumin and normal saline as the replacement solutions. Chemotherapy was either melphalan and prednisone taken daily for 4 days every 28 days for up to 12 cycles or 4 days of slow intravenous infusion of VAD given on days 1 to 4, 9 to 12, and 17 to 20 for 28-day cycles up to 6 cycles. For participants allocated to plasma exchange, we stopped VAD treatment 1.5 hours before the plasma exchange and did not give VAD treatment during the plasma exchange. After the plasma exchange, patients received a bolus volume of VAD that would have been the amount infused during this time. Measurements We assessed the following blood and urine test results at study entry and at 1 and 6 months: serum creatinine, serum calcium, serum albumin, and 24-hour urine for protein levels. We used DurieSalmon staging to classify the severity of multiple myeloma at presentation, and we estimated GFR by using the Modified Diet in Renal Disease (MDRD) equation (26, 27). Our primary outcome, assessed at 6 months, was a composite measure that included death, dialysis dependence, and an estimated GFR less than 0.29 mLs2m2 (<30 mL/min per 1.73 m2) calculated from the 6-month serum creatinine level. We included this GFR as a component of the outcome because this degree of kidney impairment is associated with increased risk for death, cardiovascular events, and hospitalization (28). Statistical Analysis On the basis of historical data, which suggested a probable event rate greater than 50%, we calculated a sample size that would detect an effect of plasma exchange on dialysis dependence, without informative censoring from death, at 6 months (4, 17, 19). To detect a difference of 50% in that outcome with a type 1 error of 0.05 (2-sided) and a type 2 error probability of 0.20, we required a sample size of 46 participants per group. We used this historical-based power analysis to provide a conservative estimate of sample size to detect a statistically significant difference in the composite outcome of death, dialysis dependence, or a GFR less than 0.29 mLs2m2 (<30 mL/min per 1.73 m2) in our future study. The safety subcommittee conducted an interim analysis when the fiftieth participant had completed the 6-month follow-up to prevent some patients from unnecessarily receiving a less effective treatment. The committee evaluated differences between the plasma exchange and control groups, with respect to the primary composite and secondary outcomes at 6 months by using Pearson chi-square. The committee evaluated the time to death by treatment groups by using KaplanMeier survival analysis with a log-rank test for differences between groups. It conducted univariate and multivariate modeling of death and composite outcomes by using logistic regression to determine the unadjusted and adjusted odd ratios for the selected baseline determinants of chemotherapy, dialysis, age, urine protein level, serum albumin level, and DurieSalmon stage for plasma exchange (29). The committee performed these secondary analyses to determine which factors, if any, influenced outcomes. No variables were missing for analyses, except for age of 1 patient, which reduced our GFR determination to 57 of 58 patients in the plasma exchange group. We conducted all statistical analyses by using the Statistical Package for the Social Sciences (SPSS), version 12.0 for Windows (SPSS, Inc., Chicago, Illinois). All significance testing used 2-tailed tests, reflecting the open-ended research hypothesis. Role of the Funding Source The Canadian Institute of Health Research, Gambro BCT, and The Kidney Foundation of Canada funded the trial. The funding sources had no role in the design, conduct, or reporting of the study or in the decision to submit the paper for publication. Gambro BCT has a direct financial interest in the study outcome since they are the purveyor of the Gambro Spectra, which was the cell separator used in the trial. Results Of 104 patients who were initially enrolled in the study, 7 were withdrawn. Of these 7 patients, 3 were ineligible and 4 were lost to follow-up (Figure 1). Among the 4 patients lost to follow-up, 1 was a homeless person and the other 3 withdrew from all medical care and follow-up after diagnosis. Thus, intention-to-treat analyses included 58 patients in the plasma exchange group and 39 patients in the conventional therapy control group. No patient crossed over from his or her treatment assignment group during the trial, and all 58 patients randomly assigned to receive plasma exchange received 5 to 7 treatments. Figure 1. Flow of patients through the study to death or dialysis dependence. Baseline characteristics were similar between groups (Table 1). Forty-three participants had a monoclonal , 36 participants had a monoclonal , and the remainder had a monoclonal BenceJones protein in excess. The monoclonal protein occurred in both the plasma and urine in 59 participants, in the plasma in 76 participants, in the urine in 79 participants, and in the casts of the renal biopsy in 1 participant. Table 1. Baseline Charact

Contrast-Induced Nephropathy and Long-Term Adverse Events: Cause and Effect?

BACKGROUND AND OBJECTIVES The relationship of contrast-induced nephropathy (CIN) to long-term adverse events (AEs) is controversial. Although an association with AEs has been previously reported, it is unclear whether CIN is causally related to these AEs. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We obtained long-term (> or =1 yr) follow-up on 294 patients who participated in a randomized, double-blind comparison of two prevention strategies for CIN (iopamidol versus iodixanol). A difference in the incidence of AEs between patients who had developed CIN and those who had not was performed using a chi(2) test and Poisson regression analysis. A similar statistical approach was used for the differences in AEs between those who received iopamidol or iodixanol. Multiple definitions of CIN were used to strengthen and validate the results and conclusions. RESULTS The rate of long-term AEs was higher in individuals with CIN (all definitions of CIN). After adjustment for baseline comorbidities and risk factors, the adjusted incidence rate ratio for AEs was twice as high in those with CIN. Randomization to iopamidol reduced both the incidence of CIN and AEs. CONCLUSIONS The parallel decrease in the incidence of CIN and AEs in one arm of this randomized trial supports a causal role for CIN.

Contrast-induced nephropathy in patients with chronic kidney disease undergoing computed tomography: a double-blind comparison of iodixanol and iopamidol.

Background:Based on a single clinical trial, it has been suggested that the contrast agent iodixanol, which is isotonic to human plasma, may be less nephrotoxic than other nonionic contrast agents in renally impaired patients after intra-arterial injection. We compared the effects on renal function of iopamidol-370 injection (796 mOsm/kg) and iodixanol-320 (290 mOsm/kg) in patients with chronic kidney disease undergoing contrast-enhanced multidetector computed tomography (CE-MDCT) examinations using a multicenter, double-blind, randomized, parallel-group design. Methods:A total of 166 patients with stable moderate-to-severe chronic kidney disease (screening and baseline serum creatinine, SCr, ≥1.5 mg/dL and/or creatinine clearance, CrCl, ≤60 mL/min) who were undergoing CE-MDCT of the liver or peripheral arteries were randomized to receive equi-iodine IV doses (40 gI) of either iopamidol-370 (370 mgI/mL) or iodixanol-320 (320 mgI/mL) at 4 mL/s. SCr and CrCl were obtained at screening, baseline, and at 48–72 ± 6 hours after dose (mean, 57.4 hours). Contrast-induced nephropathy (CIN) was defined as an absolute increase ≥0.5 mg/dL (44.2 &mgr;mol/L) and/or a relative increase in SCr ≥25% from baseline. Results:A total of 153 patients were included in the final analysis (13 patients excluded because of lack of follow-up, hemodialysis to remove contrast, average daily CrCl variation >1% at screening). The 2 study groups were comparable with regard to age, gender distribution, the presence of diabetes, concomitant medications, hydration, and contrast dose. Mean predose SCr was 1.6 ± 0.4 mg/dL in both groups (P = 0.9). An absolute increase ≥0.5 mg/dL (44.2 &mgr;mol/L) in SCr was observed in none of the patients receiving iopamidol-370 and in 2.6% (2/76) of patients receiving iodixanol-320 (95% confidence interval −6.2, 1.0, P = 0.2). A relative increase ≥25% in SCr occurred in 4% (3/77) of patients receiving iopamidol-370 and in 4% (3/76) of the patients receiving iodixanol-320 (95% confidence interval −6.2, 6.1, P = 1.0). Conclusion:The rate of CIN was similarly low in risk patients after intravenous administration of iopamidol-370 or iodixanol-320 for CE-MDCT.

Canadian Association of Radiologists Consensus Guidelines for the Prevention of Contrast-Induced Nephropathy: Update 2012

Purpose Contrast-induced acute kidney injury or contrast-induced nephropathy (CIN) is a significant complication of intravascular contrast medium (CM). These guidelines are intended as a practical approach to risk stratification and prevention. The major risk factor that predicts CIN is pre-existing chronic kidney disease. Methods Members of the committee represent radiologists and nephrologists across Canada. The previous guidelines were reviewed, and an in-depth up-to-date literature review was carried out. Results A serum creatinine level (SCr) should be obtained, and an estimated glomerular filtration rate (eGFR) should be calculated within 6 months in the outpatient who is stable and within 1 week for inpatients and patients who are not stable. Patients with an eGFR of ≥ 60 mL/min have an extremely low risk of CIN. The risk of CIN after intra-arterial CM administration appears be at least twice that after intravenous administration. Fluid volume loading remains the single most important measure, and hydration regimens that use sodium bicarbonate or normal saline solution should be considered for all patients with GFR < 60 mL/min who receive intra-arterial contrast and when GFR < 45 mL/min in patients who receive intravenous contrast. Patients are most at risk for CIN when eGFR < 30 mL/min. Additional preventative measures include the following: avoid dehydration, avoid CM when appropriate, minimize CM volume and frequency, avoid high osmolar CM, and discontinue nephrotoxic medications 48 hours before administration of CM.

Prediction of early death in end-stage renal disease patients starting dialysis

Demand for dialysis for patients with end-stage renal disease is growing, as is the comorbidity of dialysis patients. Accurate prediction of those destined to die quickly despite dialysis could be useful to patients, providers, and society in making decisions about starting dialysis. To determine whether age and comorbidity accurately predict death within 6 months of first dialysis for end-stage renal disease, a prospective cohort study of 822 patients starting dialysis at one of 11 Canadian centers was performed. Patient characteristics were recorded at first dialysis. Follow-up continued until death or study end (at least 6 months after enrollment). One hundred thirteen of 822 (13.7%) patients died within 6 months. Although an existing scoring system predicted prognosis, adverse scores greater than 9 were found in only 9.7% of those who died; only 52% of those who scored higher than 9 died within 6 months. No score cutoff point combined high true-positive and low false-positive rates for predicting early death. Age, severity of heart failure or peripheral vascular disease, arrhythmias, malnutrition, malignancy, or myeloma were independent prognostic factors identified in multivariate models. However, the best fit discriminant and logistic models were also unable to accurately predict death within 6 months. Clinicians were very accurate in assigning patients to prognostic groups up to a 50% risk of death by 6 months, above which they tended to overestimate risk. However, clinicians were only marginally better than the predictive models in determining whether a given high-risk patient would die. The inability of a scoring system or clinical intuition to accurately predict death soon after starting dialysis for end-stage renal disease suggests that limiting access to dialysis on the basis of likely short survival may be inappropriate in Canada.

A Comparison of Nonionic, Low-Osmolality Radiocontrast Agents with Ionic, High-Osmolality Agents during Cardiac Catheterization

BACKGROUND Nonionic, low-osmolality radiocontrast agents are used frequently because they are believed to be safer than ionic, high-osmolality agents, but they are also more expensive. We conducted a randomized trial to compare the incidence of adverse events after the administration of ionic, high-osmolality and of non-ionic, low-osmolality radiocontrast agents during cardiac angiography. METHODS We compared the need to treat patients for adverse reactions and the frequency and severity of specific hemodynamic, systemic, and symptomatic side effects in two groups of patients randomly assigned to receive either ionic, high-osmolality or nonionic, low-osmolality radiocontrast material, and also in 366 patients who could not be randomized. RESULTS Treatment for adverse events was required in 213 of 737 patients who received high-osmolality contrast agents (29 percent) but in only 69 of 753 patients who received nonionic agents (9 percent) (95 percent confidence interval for the percent difference, 15.9 to 23.6 percent). Hemodynamic deterioration and symptoms also occurred more often in the high-osmolality group, as did severe or prolonged reactions (2.9 percent, as compared with 0.8 percent in the nonionic group; P = 0.035). The severe reactions were largely confined to patients with severe cardiac disease. Multivariate analysis showed that the presence of severe coronary disease and unstable angina were predictors of clinically important adverse reactions. If all the patients in our randomized trial had been given nonionic contrast material, the incremental cost per procedure would have been

The Challenge of Diagnosing Atheroembolic Renal Disease: Clinical Features and Prognostic Factors

89. CONCLUSIONS Nonionic, low-osmolality contrast material is better tolerated during cardiac angiography than ionic, high-osmolality contrast material. Since cost constraints may prevent the universal use of nonionic contrast material, its selective use in patients with severe cardiac disease could be considered.