Reduced Creatinine Clearance Research Articles

Older living donors provide excellent quality kidneys: a single center experience (older living donors)

The role of advanced age live donors remains controversial because of decline in glomerular filtration rate and perceived increased risks of perioperative complications. A retrospective review of all live donor transplants performed from January 2000 to December 2003. Seventy-eight live donor transplants were performed during the period of review, 47 (60.3%) female and 31 (39.7%) male. Twenty-two (28.2%) of the donors were >50 yr old, 15 (68%) female and seven (32%) male. Living related donation was performed in 56 (74.4%) and unrelated in 20 (35.6%). Laparoscopic nephrectomy was performed in 29 (37.2%) and open nephrectomy in 49 (62.8%). More donors >50 underwent laparoscopic nephrectomy, 13 of 22 (59.1%) vs. 16 of 56 (28.6%). Overall patient and graft survival at 1 yr are 97 and 97%. One-year patient and graft survival is 100% vs. 96% and 100% vs. 96% in the older vs. young donors. Rejection occurred in nine of 78 (11.5%), but was not different between groups. Older donors had a reduced creatinine clearance 107.5 +/- 3.4 vs. 124.2 +/- 3.1 mL/min (p = 0.002) and a reduced clearance normalized for body surface area 60.6 +/- 3.6 mL/(min m2) vs. 70.2 +/- 2.6 mL/(min m2) (p = 0.045). Recipient serum creatinine was higher on postoperative day 1 in the older donor group 5.4 mg/dL vs. 4.4 mg/dL (p = 0.009). There was no difference in recipient serum creatinine at postoperative day 7, 30, 90, 180, 365 and 730. Donor serum creatinine was not different between groups on postoperative days 1, 7 and 30 but was higher in group 1 vs. group 2 on postoperative day 365, 1.26 +/- 0.26 mg/dL vs. 1.01 +/- 0.18 mg/dL (p = 0.020). Despite a reduced initial creatinine clearance, renal function is comparable in recipients of both young and old donor kidneys. Older donors had a slightly reduced serum creatinine 1 yr post-donation that warrants additional follow-up to determine if the observations continue. The introduction of laparoscopic nephrectomy may provide additional incentive for older donors to present for live donor nephrectomy.

Epidemic glomerulonephritis due to Streptococcus zooepidemicus in Nova Serrana, Brazil

In 1998, there was a large outbreak of acute glomerulonephritis in Nova Serrana, Brazil, caused by group C Streptococcus zooepidemicus. This article reviews the characteristics of the outbreak and some aspects of the patients' follow-up. We describe clinical characteristics of patients with acute nephritis. Using case-control studies, we identified the source of infection. Cultures of oropharyngeal swabs from patients were performed. Of 135 patients identified in 1998, available patients were reexamined in a prospective study after 2 and 5 years. Lancefield group C S. zooepidemicus was identified as the causative organism and linked to the consumption of cheese produced from unpasteurized milk. Of the original group of 134 patients, 4 died in the acute phase and 5 (3.7%) required chronic dialysis. After 2 years, of the 69 cases reevaluated, 94% were adults (mean +/- standard error age: 39 +/- 2 years); we found arterial hypertension in 42% (N= 27/64) of the patients, reduced creatinine clearance (<80 mL/min/1.73 m(2)) in 30% (N= 20/67), and increased microalbuminuria (>20 microg/min) in 34% (N= 22/65). Preliminary data at 5-year follow-up suggest that the percentage of patients with creatinine clearance lower than 60 mL/min increased from 9% to 15%. This article highlights the dangers of consuming unpasteurized dairy products. Follow-up of patients with epidemic poststreptococcal glomerulonephritis due to S. zooepidemicus show that a considerable proportion present hypertension, reduced renal function, and increased microalbuminuria.

Mild Renal Dysfunction and Renal Vascular Resistance in Primary Hypertension

Mild renal dysfunction (MRD) is an often overlooked but relatively common condition in patients with primary hypertension (PH), and is associated with high cardiovascular morbidity and mortality. Whether MRD is also associated with abnormalities in renal vascular resistance is currently unknown. Two hundred ninety-one untreated patients with PH were studied. The MRD was defined as a creatinine clearance >or=60 mL/min but <90 mL/min (Cockcroft-Gault formula) or the presence of microalbuminuria. Albuminuria was measured as the albumin-to-creatinine ratio in first morning urine samples. Renal resistive index (RI) was evaluated by ultrasound Doppler of the interlobar arteries. The prevalence of MRD in our cohort was 63%. Patients with MRD were older, had higher mean blood pressure (BP), pulse pressure, and total cholesterol, longer history of hypertension, and were more likely to be men. Renal RI was positively related to female gender, age, systolic BP, pulse pressure, total cholesterol, albuminuria, and to carotid wall thickness and cross-sectional area, whereas it was inversely related to diastolic BP and creatinine clearance. Patients with the highest renal resistance (upper quartile, >or=0.63) showed a greater prevalence of renal dysfunction (P=.0005). After adjusting for age, pulse pressure, and LDL-cholesterol, we found that the risk of MRD increased twofold (P=.04) when renal RI was >or=0.63. A reduction in creatinine clearance and the presence of microalbuminuria are associated with increased renal vascular impedence, as well as with signs of extrarenal arterial stiffness.

A soy diet accelerates renal damage in autoimmune MRL/Mp- lpr/ lpr mice

Isoflavones, which are phytoestrogens present in large quantities in soy and soy-derived products, have estrogenic activity, inhibit protein tyrosine kinase, and exert other effects in the human body. Thus, the recent spread of soy consumption in Western populations emphasizes the need to more fully understand the potential effects in the body, especially in abnormal immune conditions. In the present study, the influence of a soy diet on lupus disease in MRL/Mp- lpr/ lpr (MRL/ lpr) mice was investigated. Weanling female MRL/ lpr mice (4 weeks) were fed a soy diet (20% soybean protein and 5% soybean oil). The soy diet exacerbated renal damage; findings in this mouse strain included accelerated proteinuria, elevated serum creatinine concentrations, and reduced creatinine clearance. No effects were detected, however, in C3H/HeN mice, which have the same H-2 k genetic background as MRL/ lpr mice do. A tendency toward an increase in thymus weight and proliferation of T cells in spleen and B cells in lymph nodes were found at the age of 16 weeks. These findings indicate that a soy diet, in comparison with a casein diet, significantly exacerbates the clinical course of this autoimmune disease. Further research on the mechanism of this effect of soy-rich diets is needed, and isoflavone supplementation for systemic lupus erythematosus patients should be carefully reevaluated.

Five-year follow-up of patients with epidemic glomerulonephritis due to Streptococcus zooepidemicus

In 1998 there was a large outbreak of acute glomerulonephritis in Nova Serrana, Brazil, caused by group C Streptococcus zooepidemicus. This study describes the follow-up of these patients, after a mean time of 5.4 years of the acute episode. Of 135 cases identified in 1998, 56 were re-examined in a prospective study and had measurements of blood pressure, creatinine clearance (estimated by the Cockcroft and Gault formula), microalbuminuria (radioimmunoassay), urine sediment analysis and a protein dipstick test. Of the original group of 135 subjects, 3 died in the acute phase and 5 (3.7%) required chronic dialysis. Of the 56 cases re-evaluated, 54 (96%) were adults (mean+/-SD age, 43+/-17 years) and 36 (64%) females. At the follow-up examination, we found arterial hypertension in 30% (n = 17/56) of the subjects, reduced creatinine clearance (<80 ml/min) in 49% (n = 26/53) and increased microalbuminuria (>20 microg/min) in 22% (n = 11/51). Compared to the evaluation carried out 3 years before, the number of cases with creatinine clearance lower than 80 ml/min increased from 20 to 26 (of 53 cases). Increased microalbuminuria and/or reduced creatinine clearance were detected in 57% (n = 32/56) of the subjects. Patients with reduced creatinine clearance were older than those without reduced renal function (54+/-15 vs 34+/-12 years, P<0.001). After a mean time of 5.4 years, a relatively high proportion of patients with epidemic poststreptococcal glomerulonephritis due to S.zooepidemicus present hypertension, reduced renal function and increased microalbuminuria.

Editorial Comment: Reduction in Calcineurin Inhibitor Exposure and Maintenance of Effective Immunosuppression: Clinical Experience with Everolimus (Certican)

Editorial Comment: Reduction in Calcineurin Inhibitor Exposure and Maintenance of Effective Immunosuppression: Clinical Experience with Everolimus (Certican)

Safety and Effectiveness of Gadolinium-enhanced Multi–Detector Row Spiral CT Angiography of the Chest: Preliminary Results in 37 Patients with Contraindications to Iodinated Contrast Agents

To prospectively evaluate the safety and effectiveness of gadolinium-enhanced multi-detector row spiral computed tomographic (CT) angiography of the pulmonary circulation by using two gadolinium doses in patients with contraindications to iodinated contrast agents. Study was approved by the Ethics Committee, and written informed consent was obtained. Thirty-seven patients (20 men, 17 women) with contraindications to iodinated contrast agents (allergic reactions, n = 27; impaired renal function, n = 10) underwent CT angiography of the pulmonary circulation in search of acute pulmonary embolism (n = 28) or for management of tumoral disease (n = 9). CT angiography was performed (a) with four-detector row (n = 19) or 16-detector row (n = 18) scanners; (b) at randomly assigned gadolinium doses of either 0.3 mmol per kilogram of body weight (n = 19) or 0.4 mmol/kg (n = 18); and (c) with a systematic evaluation of clinical and biologic tolerance of gadolinium. Comparison of percentages between group 1 and group 2 scans was performed with the chi2 or the Fisher exact test. An unpaired Wilcoxon rank sum test was used for numeric variables. P < .05 was considered to indicate a significant difference. The mean (+/- standard deviation) volume of gadopentetate dimeglumine administered in the overall study group was 48 mL +/- 9.6 (range, 29-65 mL). The level of maximal enhancement in the pulmonary arteries was significantly higher in group 2 than in group 1 (215.8 HU +/- 95 vs 141.3 HU +/- 44) (P = .02) and was maintained throughout the entire region of interest in a greater number of examinations in group 2 than in group 1 (n = 16 [89%] vs n = 2 [10.5%]) (P < .0001). The number of diagnostic CT angiograms was significantly higher in group 2 than in group 1 (n = 17 [94%] vs n = 13 [68%]) (P = .007). Significant but transient reduction of creatinine clearance was observed in one patient with preexisting moderate chronic renal failure (0.3 mmol/kg gadolinium dose). High-quality gadolinium-enhanced CT angiograms require the use of 16-detector row CT technology; the doses administered did not alter the renal function except transiently in one patient.

Valganciclovir for the Early Prophylaxis of Cytomegalovirus (CMV) Infection after Allogeneic Stem Cell Transplantation.

Despite improvements in methods for the early diagnosis of CMV infection, 5% of HSCT patients receiving preemptive therapy develop CMV disease. In addition, the use of highly immunosuppressive therapies prior to and after transplant and the use of matched unrelated (MUD) and mismatched related (MRD) donors have increased the incidence of CMV infection and disease. We designed a prospective trial examining the safety and efficacy of valganciclovir for the prophylaxis of early CMV infection.Methods: CMV seropositive patients or CMV seronegative patients receiving CMV seropositive stem cell products with an estimated creatinine clearance of ≥ 50 mL/min, platelet count ≥ 50,000/μL, and WBC count ≥ 1,000/μL are eligible. Patients receive valganciclovir 900 mg daily Mondays through Fridays starting 21 to 35 days after transplant and continuing through Day 100, with dosage adjustments for myelosuppression and/or reduced creatinine clearance. Patients are monitored with weekly CMV PCR analysis at a central lab according to the Roche assay.Results: Twenty four (24) out of 50 planned subjects have been enrolled to date (MUD 9, MRD 15). All were CMV seropositive at the time of transplant. Stem cell source included peripheral blood = 21, bone marrow = 3. A total of 7 patients required corticosteroids for treatment of graft versus host disease. Three patients developed myeloid toxicity related to valganciclovir (absolute neutrophil count < 1,000/μL = 1, platelets < 50,000/μL = 2). All three (3) patients recovered their counts and restarted valganciclovir with dose adjustments. A total of 11 patients required dose adjustments due to myelosuppression (3), creatinine clearance (4), weight (1), institutional decision (3). Twelve (12) patients have not completed therapy due to: progressive disease or death before day +100 = 4, CMV infection =2, too early for analysis = 6. CMV infection occurred in 2/24 and CMV disease occurred in 0/24. The two (2) patients with positive CMV-PCR developed infection one (Day 40) and two (Day 36) weeks after starting valganciclovir. These two (2) patients were successfully treated with IV ganciclovir. Ten (10) patients have been followed between day +100 and 6 months post transplant. Three (3) of these 10 patients continued valganciclovir off study and had no evidence of CMV infection. Two (2) of the 10 patients who were not receiving valganciclovir developed CMV infection but were successfully treated with valganciclovir. Survival is 80% (16/20) at day +100 and 82% (9/11) at 6 months post transplant.Conclusions: We conclude that valganciclovir at the dose used in this study is well tolerated with minimal reversible myelosuppression. These preliminary findings suggest that prophylaxis with oral valganciclovir appears to be a promising strategy to prevent CMV infection and disease.

Safety and Efficacy of Venous Thromboembolism Prophylaxis with Low Molecular Weight Heparin in Hospitalised Patients with Acute Medical Illness and Renal Failure.

Objectives: To study the incidence of bleeding complications during thromboprophylaxis with dalteparin in patients with acute medical illness and renal failure.Design: Prospective, cohort study.Setting: Community Hospital.Main outcome: The primary safety outcome was the incidence of major and minor bleeding, while the primary efficacy outcomes were objectively verified symptomatic DVT, pulmonary embolism, and objectively verified asymptomatic DVT detected on routine compression ultrasonography. Secondary outcomes included anti-Xa heparin levels.Patients: 56 consecutives patients (29 males, age 77.86±10.27 y, 27 females, age 84.60±6,78 y) admitted with acute medical illness were considered for the study. Eligible patients were 18 years or older and had none of the following: hepatic failure (prothrombin time <50%), platelet count <100.000/ml, chronic use of warfarin, or an ongoing requirement for anticoagulation. Two doses of dalteparin were prescribed as dictated by a venous thromboembolism risk score. 44 patients judged to be at high risk (age >75 y, 44 of 56, 78%, active cancer, 5 of 56, 8.9%, previous venous thromboembolism, 1 of 56, 1.8%) received a dose of 5.000 IU daily; the other 12 received 2.500 IU daily. Dalteparin was given at 8 am for 6 days. The timing of anti-Xa activity determination and of compression ultrasound examination of leg veins is shown in table 1.MethodsResults: there was 1 case (1 of 56, 1.8%) of nose bleeding at the third day of treatment in a patient with moderate renal failure. The bled was easily stopped. None of the following variables: dose of dalteparin, age, sex, creatinine clearance, and anti-Xa activity when entered in a regression model were able to predict the hemorrhagic complication. There were no cases of venous thromboembolism. Though, peak anti-Xa activity was higher in patients with marked renal impairment, it never reached therapeutic levels (>0.5 IU/mL).anti-Xa activity at day 6Conclusions: The modest (and not significant) increase in anti-Xa activity in patients with reduced creatinine clearance was not associated with a clinically apparent risk of bleeding. Thromboprophylaxis with dalteparin appears safe even in acutely ill medical patients with renal failure.day 0Creatinine Clearanceanti-Xa activity before DalteparinCUSday 6Creatinine Clearanceanti-Xa activity 4 h after DalteparinCUSCrCl >90 ml/minCrCl >89–60 ml/minCrCl >59–30 ml/minCrCl <29 ml/minPatients5122613anti-Xa activity IU/mL0.012±0.020.016±0.0540.066±0.120.20±0.66p=0.45

Incidence and Risk Factors for In-Hospital Bleeding in Acutely Ill Medical Patients: Findings from IMPROVE.

Background We examined data from acutely ill medical patients enrolled in The International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) to determine factors that are independently associated with an increased risk of bleeding during hospitalization.Methods Patients ≥18 years old, hospitalized for ≥3 days with an acute medical illness have been enrolled consecutively since July 2002. Exclusion criteria are: therapeutic antithrombotics/thrombolytics at admission; major surgery or trauma during 3 months prior to admission; and venous thromboembolism (VTE) treatment within 24 hours of admission. Patients with bleeding immediately prior to, or at admission were excluded from this analysis. Factors considered were: age, ICU stay, reduced creatinine clearance, severe infection, cerebrovascular stroke, cancer, diabetes, severe renal failure, hypertension, lower limb paralysis, bleeding disorders, hemorrhagic stroke, thrombocytopenia, gastro-duodenal ulcer, hepatic failure, central venous catheter at admission, hormonal therapy for cancer, platelet count, BMI, immobility, and length of hospital stay. Factors increasing the risk of bleeding were identified by univariate analysis (P≤0.20) and included in a multiple logistic regression model. Factors with significance of P≤0.05 were retained in the model. Bleeding events were defined as major or clinically significant non-major according to published criteria (Büller HR et al. N Engl J Med. 2003; 349:1695–702).Results. Data were from 2816 patients enrolled up to 30 June 2004 in 34 hospitals in 10 countries. Patients were: 48% female, mean age 64 years, mean weight 72 kg, mean length of hospital stay 12 days, and 37% were immobile for ≥3 days (median duration of immobility 6 days, including immobility immediately prior to admission). Only 89 (3.2%) patients had in-hospital bleeding: 1.2% major, 1.9% clinically significant non-major, 0.1% unspecified. Factors that were independently associated with an increased risk of bleeding (major or non-major) in acutely ill medical patients are shown in Table 1.Conclusion Only 3.2% of acutely ill medical patients in IMPROVE had in-hospital bleeding. Major bleeding (1.2%) was similar to that observed in a major clinical trial on VTE prophylaxis, MEDENOX (1.0%; Samama et al. N Engl J Med. 1999; 341:793–800). Advanced age, contrary to the belief of many physicians, was not independently associated with an increased risk of bleeding. Final results will be presented with adjustment for the influence of VTE prophylaxis and antiplatelet drugs.Table 1. Factors independently associated with an increased risk of bleeding in acutely ill medical patientsFactorOR95% CIBleeding disorder8.383.53–19.90Active gastro-duodenal ulcer4.261.86–9.76Hepatic failure2.971.26–6.96Creatinine clearance <30 mL/min*2.821.61–4.93Central venous catheter2.431.43–4.14Active cancer2.221.33–3.68Length of hospital stay, per day1.031.02–1.05*compared with creatinine clearance >60 mL/min (normal renal function)

Protective effect of γ-aminobutyric acid against glycerol-induced acute renal failure in rats

To investigate the effect of γ-aminobutyric acid (GABA) on acute renal failure, we used a rat model of acute tubular necrosis induced by glycerol. After deprivation of water for 6h, the rats received an injection of 50% glycerol into the muscle of the rear limb at 10ml/kg body weight. GABA was then administered orally to the rats (100 or 500mg/kg body weight/day) once every 12h for 3 days. The rats with acute renal failure showed arrested body weight gain and an increase of kidney weight, whereas oral administration of GABA attenuated the physiological changes induced by acute renal failure. However, GABA administration had no significant effect on increased urine volume. Oral administration of GABA at a dose of 100 or 500mg/kg body weight/day for 3 days significantly improved the markedly elevated levels of blood urea nitrogen and creatinine and the reduced creatinine clearance related to progression of renal failure. Moreover, the rats with acute renal failure exhibited high levels of fractional excretion of sodium (FENa) due to alteration of tubule function following injection of glycerol. However, administration of GABA lowered the FENa levels dose-dependently. Furthermore, urine osmolarity was markedly reduced in control rats with acute renal failure as compared with normal rats, whereas it was significantly increased by administration of GABA at a dose of 500mg/kg body weight/day. These results indicate that GABA has potential as a therapeutic agent against the renal damage involved in acute renal failure.

A randomized controlled trial of intravenous N-acetylcysteine for the prevention of contrast-induced nephropathy after cardiac catheterization: Lack of effect

Background Contrast-induced nephropathy (CIN) after cardiac catheterization is common in patients with preexisting renal dysfunction. Studies of oral acetylcysteine to prevent CIN have produced conflicting results. Intravenous N-acetylcysteine (NAC) has logistic advantages in this setting. The objective of this study was to evaluate, in a blinded, randomized, placebo-controlled fashion, whether intravenous NAC reduced CIN in the setting of cardiac catheterization in patients with preexisting renal insufficiency. Methods Patients with renal dysfunction undergoing cardiac catheterization were randomly assigned to intravenous NAC 500 mg immediately before the procedure or placebo. All patients received isotonic saline (200 mL) beforehand, followed by 1.5 mL/kg per hour for 6 hours, unless contraindicated. Exclusion criteria included acute renal failure, creatinine >400 μmol/L, concurrent dialysis, unstable clinical status, and prior NAC use. Baseline creatinine was obtained immediately before the procedure and repeated 2 to 8 days later. The primary end point was the occurrence of CIN defined as a reduction in creatinine clearance from baseline of >5 mL/min (Cockcroft-Gault formula). Results The study was terminated early because of a determination of futility by the Data Safety Monitoring Committee after enrollment of 487 patients. The median baseline creatinine clearance was 44 mL/min (interquartile range, 33, 55). Median contrast received was 120 mL (interquartile range, 80, 175). Baseline characteristics were similar in the two groups. Altogether, 98 (22.0%) subjects had the primary end point: 23.3% in the NAC group and 20.7% in the placebo arm ( P = .57). Conclusions In this large, randomized trial, enrolling a high-risk group of patients with impaired renal function, intravenous NAC was ineffective in preventing CIN.

Creatinine clearance but not serum creatinine alone predicts long-term postoperative survival

Abstract Introduction: End-stage renal disease is a risk factor for perioperative morbidity and shortened survival after major surgery. Given the multiple confounding factors related to serum creatinine, we aimed to determine if estimated creatinine clearance more accurately predicts long-term survival. Methods: We retrospectively reviewed the vascular registry at our institution. Logistic regression analysis was conducted to determine independent predictors of one-, two-, and three-year mortality. Creatinine clearance was calculated as [[140-age(yr)]∗weight(kg)]/[72∗serum Cr(mg/dL)] (multiplied by 0.85 for women). Results: 252 patients underwent infrainguinal bypass procedures between August 1999 and May 2000. Demographics included average age 68 years, 65% male, 74% diabetic, 12% dialysis-dependent, 23% history of CHF, 12% history of stroke, and 20% serum creatinine >2mg/dL. One-, two-, and three-year mortalities were 16%, 25%, and 35%, respectively. Creatinine did not differ between survivors and non-survivors at one year (1.8 vs 1.9, p=0.802), two years (1.8 vs 2.0, p=0.618), or three years (1.8 vs 2.0, p=0.241), and creatinine >2mg/dL did not predict long-term adverse outcomes. In contrast, reduced creatinine clearance (60 ml/min) was an independent predictor of mortality regardless of dialysis statis (1-yr: OR=2.53, p=0.014; 2-yrs: OR=2.46, p=0.004; 3-yrs: OR=2.45, p=0.001), and creatinine clearance was higher for survivors at all three time points (1-yr: 70.2 vs 49.5, p=0.003; 2-yrs: 72.3 vs 51.2, p Conclusions: Regardless of dialysis status, a decreased creatinine clearance, but not elevated creatinine alone, is an independent predictor of postoperative mortality. This measure should be included in preoperative risk evaluations of patients undergoing major surgical procedures.

Orqis® Cancion® Cardiac Recovery System: Hemodynamic Effects of a Novel Minimally–Invasive Approach to Cardio-renal Support in Severe Acute Heart Failure

Background: The Cancion® Cardiac Recovery System (CRS) is a novel, percutaneous, low flow circuit, superimposing non-pulsatile flow in the descending aorta. This abstract reports the impact of this device on cardiac hemodynamics in 23 patients. Methods: Entry criteria included: 1) recently exacerbated chronic heart failure (CHF); 2) sustained (>24hr) elevated PCWP despite IV inotropes; 3) reduced creatinine clearance and/or diuretic resistance. Inflow to the miniature centrifugal pump was via percutaneous femoral artery cannula, and outflow was via percutaneous aortic pigtail cannula (n=19) or axillary graft cannula (n=4). Cath lab insertion was<30 minutes. Hemodynamics were measured at baseline, every 8 hrs on device, and 12 and 24 hrs post device removal. Results: CRS was placed in 23 patients. Mean age was 55 (26–75) yrs. Patients were supported for an average of 73 (24–112) hrs. Pump flows averaged 1.33 (1.2–1.5) l/min. Mean PCWP decreased from 28±5 to 22±9 mmHg at 24 hrs and 20±7 mmHg at 72 hrs post-implant (both p<0.005). Mean Cardiac Index (CI) was 1.97±0.46 and 2.06±0.39 l/min/m2 at baseline and 24 hrs, and increased to 2.24±0.45 l/min/m2 72 hrs post implant (p<0.05). 24 hrs post-removal, hemodynamic benefit was sustained: PCWP 21±7 mmHg; CI 2.32±0.47 l/min/m2 (both p<0.0001 vs. baseline) representing marked, sustained favorable shift in the Starling relation. (See Figure.) By day 4 post-implant cumulative input-output averaged -3.5L and weight loss averaged 2.2 (0–7.5) Kg. Conclusion: The Cancion® CRS, a novel form of cardiac assist, acting through a low-flow, continuous aortic flow loop, induced progressive improvement in hemodyanamics, with both improved cardiac performance (shift in Starling relation) and negative fluid balance, in patients with exacerbated CHF. CRS, undergoing prospective, randomized, long-term investigation, represents a promising therapy for patients refractory to, or dependent on, IV inotropes.

Use of pharmacogenomics in predicting bleomycin-induced pulmonary toxicity in testicular cancer patients

4531 Background:Use of bleomycin, important for treatment efficacy in testicular cancer, is limited by its pulmonary toxicity. Bleomycin is mainly excreted by the kidneys, but can also be inactivated by bleomycin hydrolase (BLH). An A1450G polymorphic site in the BLH gene results in an amino acid substitution in the C-terminal domain of the protein. Deletion of this domain reduces enzymatic activity. We investigated whether the homozygote polymorphic BLH genotype increases sensitivity to bleomycin and risk of bleomycin-induced pulmonary toxicity (BIP) in testicular cancer patients. METHODS: For all patients with testicular cancer treated with bleomycin combination chemotherapy at our institution between 1977 and 2003, data were collected on age, pretreatment creatinine clearance, and occurrence of BIP, which was defined as: death due to BIP, or clinical and/or radiographic signs of BIP either following treatment or during treatment leading to cessation of bleomycin administration. PCR and restriction fragment length polymorphism were used to determine A/A (wild-type), A/G, and G/G (two polymorphic alleles, possibly reduced enzymatic activity)genotypes. RESULTS: Both genotype and clinical data were available for 246 patients (60% of cohort; median age 29 yrs, range 16-64; median cumulative bleomycin dose 270 mg, range 60-360; median pretreatment creatinine clearance 122 ml/min, range 64-202), of whom 27 (11%) had BIP. A/A, A/G, and G/G genotype frequencies were 41.9%, 48.4% and 9.7%. G/G genotype distribution did not differ between patients with and without BIP (7.4% versus 10.0%; odds-ratio G/G versus A/A genotype: 0.53, 95% confidence interval 0.11-2.51). Patients with BIP had a lower creatinine clearance. CONCLUSIONS: Compared with patients without BIP, patients with BIP were not more likely to have a G/G than an A/A genotype. However, effects of BLH genotype may become visible in patients with markedly reduced creatinine clearance. Supported by grants from the Dutch Cancer Society and the University Hospital Groningen. No significant financial relationships to disclose.

Use of pharmacogenomics in predicting bleomycin-induced pulmonary toxicity in testicular cancer patients

4531 Background:Use of bleomycin, important for treatment efficacy in testicular cancer, is limited by its pulmonary toxicity. Bleomycin is mainly excreted by the kidneys, but can also be inactivated by bleomycin hydrolase (BLH). An A1450G polymorphic site in the BLH gene results in an amino acid substitution in the C-terminal domain of the protein. Deletion of this domain reduces enzymatic activity. We investigated whether the homozygote polymorphic BLH genotype increases sensitivity to bleomycin and risk of bleomycin-induced pulmonary toxicity (BIP) in testicular cancer patients. Methods:For all patients with testicular cancer treated with bleomycin combination chemotherapy at our institution between 1977 and 2003, data were collected on age, pretreatment creatinine clearance, and occurrence of BIP, which was defined as: death due to BIP, or clinical and/or radiographic signs of BIP either following treatment or during treatment leading to cessation of bleomycin administration. PCR and restriction fragment length polymorphism were used to determine A/A (wild-type), A/G, and G/G (two polymorphic alleles, possibly reduced enzymatic activity)genotypes. Results:Both genotype and clinical data were available for 246 patients (60% of cohort; median age 29 yrs, range 16–64; median cumulative bleomycin dose 270 mg, range 60–360; median pretreatment creatinine clearance 122 ml/min, range 64–202), of whom 27 (11%) had BIP. A/A, A/G, and G/G genotype frequencies were 41.9%, 48.4% and 9.7%. G/G genotype distribution did not differ between patients with and without BIP (7.4% versus 10.0%; odds-ratio G/G versus A/A genotype: 0.53, 95% confidence interval 0.11–2.51). Patients with BIP had a lower creatinine clearance. Conclusions:Compared with patients without BIP, patients with BIP were not more likely to have a G/G than an A/A genotype. However, effects of BLH genotype may become visible in patients with markedly reduced creatinine clearance. Supported by grants from the Dutch Cancer Society and the University Hospital Groningen. No significant financial relationships to disclose.

OLDER DONORS PROVIDE EXCELLENT QUALITY KIDNEYS IN LIVE DONATION

A44 Aims: This single center retrospective review seeks to examine the results of live donor kidney transplantation from donors greater than 50 years old. Methods: The charts of all live donors and their recipients were reviewed from January 2000 until November 2003. Donor charts were reviewed for preoperative creatinine clearance, serum creatinine, postoperative serum creatinine at defined time intervals, method of nephrectomy, complications and length of stay. Recipient charts were reviewed for serum creatinine, length of stay, occurrence of rejection, complications, patient and graft survival. Donors aged greater than 50 years are considered the study group. Results: 78 live donor transplants were performed during the period of review, 47 (60.3%) female and 31 (39.7%) male. 22 (28.2%) of the donors were greater than 50 years old, 15 (68%) female and 7 (32%) male. Living related donation was performed in 56 (74.4%) and unrelated in 20 (35.6%). Laparoscopic nephrectomy was performed in 29 (37.2%) and open nephrectomy in 49 (62.8%). More donors greater than 50 underwent laparoscopic nephrectomy, 13/22 (59.1%) vs 16/56 (28.6%) in the young group (p=0.013). Rejection occurred in 9/78 (11.5%), but was not different between groups. Overall patient and graft survival at 1 year are 97% and 97%. One-year patient and graft survival is 100% vs 96% and 100% vs 96% in the older vs young donors. Older donors had a reduced creatinine clearance 107cc/min vs 126cc/min (p=.007). There was no difference in preoperative or postoperative serum creatinine at day 1,7 and 30 in the older and young donor groups. Recipient serum creatinine was higher on postoperative day 1 in the older donor group 5.4mg/dl vs 4.4mg/dl (p=0.042). There was no difference in recipient serum creatinine at postoperative day 7,30,90,180 and 365. Donor length of stay was 3.0 vs 3.3 days and recipient length of stay was 4.8 vs 5.7 days in older vs young donor groups (p=ns). No complications occurred in the older donor group. Six (7.7%) young donors developed wound complications, 4 hernias requiring surgical repair and 2 infections treated with antibiotics (p=ns). Conclusions: Donors greater than 50 years of age are suitable for living kidney donation. They do not experience a higher incidence of perioperative complications. Despite a reduced initial creatinine clearance, renal function is comparable in recipients of both young and old donor kidneys. The introduction of laparoscopic nephrectomy may provide additional incentive for older donors to present for live donor nephrectomy.

Indiana University School of Medicine.

Indiana University School of Medicine.

Analysis of renal function after aneurysm repair with a device using suprarenal fixation (zenith AAA endovascular graft) in contrast to open surgical repair

Purpose This study was undertaken to assess the effect on renal function of open surgery and endovascular abdominal aortic aneurysm (AAA) repair with suprarenal fixation with the Zenith device. Methods Data for 279 patients with similar preoperative comorbid conditions were prospectively analyzed after AAA repair. One hundred ninety-nine patients underwent endografting with the Zenith AAA Endovascular Graft, which incorporates suprarenal fixation (Zenith standard risk group, ZSR), and 80 patients underwent open surgery (standard surgical risk group, SSR). Endovascular repair was also performed in 100 patients considered poor candidates for open repair (Zenith high risk group, ZHR). Serum creatinine concentration (SCr) and anatomic defects were assessed before the procedure, before discharge, and at 1, 6, 12, and 24 months in all patients who underwent endovascular repair, and before the procedure and at 1 and 12 months in patients who underwent open surgical repair (only SCr was measured before discharge). Renal function was also analyzed, with a creatinine clearance calculation (Cockcraft-Gault). Renal insufficiency was defined as an increase in SCr greater than 30% from a preoperative baseline value, any SCr concentration in excess of 2.0 mg/dL, or any need for dialysis. Cumulative renal infarction and arterial occlusion rates were calculated with computed tomographic, ultrasonographic, and angiographic data, and reported as cumulative values. Results Despite the initially superior renal function in the ZSR group at the pre-discharge evaluation ( P = .01), there were no differences at 12 months with respect to rise in SCr greater than 30% (ZSR, 16%, vs SSR, 12%; P = .67), SCr rise greater than 2.0 mg/dL (ZSR, 2.5%, vs SSR, 3.4%; P = .66), incidence of renal artery occlusion (ZSR, 1%, vs SSR, 1.4%; P > .99), or infarction (ZSR, 1.5%, vs SSR, 1.4%; P > .99). Only one patient in each group required hemodialysis. Of note, both groups of patients demonstrated a reduction in creatinine clearance over 12 months, which then stabilized or improved by 24 months for ZSR patients. Conclusions Renal dysfunction occurs in a subset of patients regardless of type of repair (open or endovascular with suprarenal fixation). The cause of renal dysfunction after open or endovascular repair with a suprarenal stent is probably multifactorial. The observed dysfunction occurs in a small number of patients, and the effect in the endovascular group (no data for the surgical group at 24 months) appears to be transient. The initial dysfunction, apparent in both groups over 12 months of follow-up, stabilizes or improves at 12 to 24 months.

Utility of endogenous creatinine clearance as a measure of renal function in mice

The use of endogenous plasma creatinine levels and creatinine clearance as a tool to evaluate renal function in mice has come under scrutiny as prior studies have reported that the Jaffé alkaline picrate method grossly overestimates true plasma creatinine in mice. As members of the NIDDK Animal Models of Diabetic Complications Consortium (AMDCC), we evaluated the performance and feasibility of an alternative high-performance liquid chromatography (HPLC)-based method for standard determination of plasma creatinine and creatinine clearance in mice. Our purpose was to develop a simple method that provides a reliable, reproducible, and sensitive assay for small volumes (<25 microL) of mouse plasma and sera. We compared creatinine clearance measured by HPLC with the Jaffé method and HPLC creatinine clearance with inulin clearance [fluoroscein isothiocyanate (FITC) inulin in an osmotic pump implanted in mouse] in C57BL/6J mice. Different groups of mice underwent either one of two protocols. Protocol A included dietary intervention with normal, low salt plus enalapril, or high salt. Protocol B induced diabetes using streptozotocin. First, mean plasma creatinine levels were significantly lower (P < 0.0001) by HPLC (0.128 +/- 0.026 mg/dL) vs. Jaffé (0.4 +/- 0.12 mg/dL) for mice on a normal diet. Urine creatinine concentrations measured by HPLC were 10% lower than by Jaffé (P < 0.01). Second, mean creatinine clearance by HPLC for mice on a normal diet was 255 +/- 68 microL/min. Mice on low salt diet plus enalapril had reduced creatinine clearance (72.8 +/- 24.2 microL/min) while mice on high salt diet had an elevated creatinine clearance (355 +/- 105 microL/min). Third, diabetic mice (19 to 24 weeks of diabetes) exhibited hyperfiltration as creatinine clearance was 524 +/- 214 microL/min whereas nondiabetic age/gender-matched mice showed a mean creatinine clearance of 206 +/- 41 microL/min. Finally, significant correlation was demonstrated for creatinine clearance by HPLC vs. inulin clearance (R= 0.643; P < 0.001). HPLC is highly accurate, much more sensitive and specific than the Jaffé method for plasma creatinine measurements in mice. Creatinine clearance in mice measured by HPLC reflects changes in renal function induced by diet and diabetes.