Reduced Creatinine Clearance Research Articles

An initial evaluation of post-cardiopulmonary bypass acute kidney injury in swine☆

Acute kidney injury (AKI) post-cardiac surgery is associated with mortality rates approaching 20%. The development of effective treatments is hindered by the poor homology between rodent models, the mainstay of research into AKI, and that which occurs in humans. This pilot study aims to characterise post-cardiopulmonary bypass (CPB) AKI in an animal model with potentially greater homology to cardiac surgery patients. Adult pigs, weighing 50-75 kg, underwent 2.5 h of CPB. Pigs undergoing saphenous vein grafting procedures served as controls. Pre-CPB measures of porcine renal function were within normal ranges for adult humans. The effect of CPB on renal function; a 25% reduction in (51)Cr-EDTA clearance (p=0.068), and a 33% reduction in creatinine clearance (p=0.043), was similar to those reported in clinical studies. CPB resulted in tubular epithelial injury (median NAG/creatinine ratio 2.6 u mmol(-1) (interquartile range (IQR): 0.81-5.43) post-CPB vs 0.48 u mmol(-1) (IQR: 0.37-0.97) pre-CPB, p=0.043) as well as glomerular and/or proximal tubular injury (median albumin/creatinine ratio 6.8 mg mmol(-1) (IQR: 5.45-13.06) post-CPB vs 1.10 mg mmol(-1) (IQR: 0.05-2.00) pre-CPB, p=0.080). Tubular injury scores were significantly higher in kidneys post-CPB (median score 2.0 (IQR: 1.0-2.0) relative to vein graft controls (median score 1.0 (IQR 1.0-1.0), p=0.019). AKI was associated with endothelial injury and activation, as demonstrated by reduced DBA (dolichos biflorus agglutinin) lectin and increased endothelin-1 and vascular cell adhesion molecule (VCAM) staining. The porcine model of post-CPB AKI shows significant homology to AKI in cardiac surgical patients. It links functional, urinary and histological measures of kidney injury and may offer novel insights into the mechanisms underlying post-CPB AKI.

Renal and cardiac abnormalities in primary hypertension

The relationship between mild reduction in renal function and cardiac structure and function have not yet been fully elucidated. We investigated cardiac and renal abnormalities in 400 untreated, nondiabetic patients (65% men, mean age 47 years) with primary hypertension and normal serum creatinine. Renal abnormalities were defined as creatinine clearance less than 75 ml/min per 1.73 m2 (Cockcroft-Gault formula) and/or the presence of microalbuminuria (albumin-to-creatinine ratio). Left ventricular structure and function were assessed by echocardiography. The prevalence of microalbuminuria and reduced creatinine clearance was 13 and 31%, respectively. Patients with renal abnormalities shared greater left ventricular mass index, higher prevalence of left ventricular hypertrophy, and unfavorable geometric patterns. Microalbuminuria was also associated with inappropriate left ventricular mass and depressed midwall fractional shortening, whereas reduced creatinine clearance was associated with lower stroke volume and higher central pulse pressure/stroke volume ratio and total peripheral resistance. Stepwise regression analysis showed that both albuminuria and creatinine clearance were independently related to left ventricular mass. Logistic regression analysis of the reciprocal interaction of microalbuminuria and reduced creatinine clearance on the occurrence of subclinical cardiac damage showed that reduced creatinine clearance entailed a greater risk of left ventricular hypertrophy in patients with normal albuminuria alone, whereas the presence of microalbuminuria was associated with a greater risk of left ventricular hypertrophy independently of creatinine clearance. These findings provide further proof of the role of cardiorenal interaction in the development of hypertension-related cardiovascular disease, and may have clinical implications.

EFFECT OF CALCIUM CHANNEL BLOCKADE ON ADRENERGICALLY INDUCED RENAL VASOCONSTRICTION IN RAT MODELS OF RENAL IMPAIRMENT

1. Calcium channel blockade attenuates adrenergically induced renal vasoconstriction and the present study examined whether the magnitude of the supression was enhanced or blunted in rat models of renal failure or diabetes-induced glomerular hyperfiltration. 2. Male Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were used that had either renal failure induced by cisplatin administration or early diabetic nephropathy (EDN) consequent to an injection of streptozotocin (STZ). After 7 days of cisplatin or 4 weeks of STZ, rats were anaesthetized and renal haemodynamic studies were performed. 3. Cisplatin-treated WKY rats and SHR exhibited reduced creatinine clearance (CCr) and increased fractional excretion of sodium (FE(Na)) and kidney index (all P < 0.05), along with tubular damage in the kidney, compared with non-treated rats. In the EDN model, there was marked albuminuria and increased FE(Na), kidney index and CCr (all P < 0.05) compared with non-diabetic nephropathy (NDN) rats. Amlodipine significantly (P < 0.05) and dose-dependently attenuated the magnitude of the neurally and adrenergically induced renal vasoconstriction in all experimental groups compared with their respective control groups (13-6 vs 9-5% in renal failure vs non-renal failure WKY rats; 26-15 vs 17-8% in renal failure vs non-renal failure SHR; 19-9 vs 14-5% in EDN vs NDN). 4. The data obtained demonstrate that not only does amlodipine blunt adrenergically induced renal vasoconstriction in normal rats, but that it also does so, and to a greater extent, in rats with either renal failure or hyperfiltration.

Stopping the Hemorrhage

Aggressive management of high-risk non–ST-elevation acute coronary syndrome patients has focused on reducing ischemic complications with potent medications and mechanical interventions1,2 but at the cost of increased rates of major bleeding and associated adverse outcomes.3,4 The American College of Cardiology/American Heart Association 2007 guidelines for management of patients with unstable angina/non–ST-elevation myocardial infarction (NSTEMI)1 stress the importance of balancing antithrombotic and interventional therapies with therapeutic risk, and they urge special attention in groups at high bleeding risk, including women, the elderly, and those with renal insufficiency. For risk-prone groups, careful selection and dose adjustment of antithrombotics is encouraged, but no specific instruction for calculating bleeding risk or modifying treatment is provided. Article p 1873 The European Society of Cardiology’s 2007 guidelines for the diagnosis and treatment of non–ST-segment elevation acute coronary syndromes2 also recognize and devote a special section to bleeding complications, covering predictors of bleeding risk, the impact of bleeding on prognosis, the management of bleeding complications, and the impact of blood transfusions on outcomes. Major bleeding has been reported in 2% to 8% of non–ST-elevation acute coronary syndrome patients, with higher rates noted in broad-based registries (as in CRUSADE: Can Rapid risk stratification of Unstable angina patients Suppress Adverse outcomes with Early implementation of the ACC/AHA guidelines) than in controlled clinical trials. Complicating therapeutic decision making is the observation that baseline predictors of bleeding, ie, old age, female sex, renal dysfunction, and baseline anemia, also predict the risk of death due to ischemic complications. The impact of bleeding on prognosis is increasingly recognized. Major bleeding in the Global Registry of Acute Coronary Events (GRACE) was significantly associated with in-hospital death (adjusted OR 1.645). In registries and trials of more than 30 000 patients, major bleeding was associated with a 4-fold increase in the …

Mycophenolate and Sirolimus as Calcineurin Inhibitor-Free Immunosuppression Improves Renal Function Better Than Calcineurin Inhibitor-Reduction in Late Cardiac Transplant Recipients With Chronic Renal Failure

Calcineurin-inhibitor-(CNI)-induced renal failure is one major cause of morbidity in cardiac transplantation (HTx). In this prospective, randomized, multicenter trial, the impact of immunosuppressive conversion toward CNI-free (mycophenolate mofetil [MMF] and sirolimus) or a CNI-reduced immunosuppressive regimen on renal function, efficacy, and safety was evaluated. Since 2004, 63 HTx-patients (0.5-18.4 years after HTx) with CNI-based immunosuppression and reduced creatinine clearance less than 60 mL/min (39+/-15 mL/min) were included in this trial. Patients in the CNI-free-Group (group 1) were converted to sirolimus that was started with 2 mg/day until target trough levels (8-14 ng/mL) were achieved. Subsequently, CNIs were withdrawn. In CNI-reduction-Group (group 2), CNI target trough levels were reduced by 40%. In both groups MMF was continued and trough level adjusted (1.5-4 microg/mL). Patients demographics and survival (mean follow-up time: 16.7+/-9 months) was equal (100%). Renal function improved significantly after complete CNI withdrawal while remaining unchanged with CNI-reduction (Creatinine clearance after 12 months: 53+/-24 mg/dL [group 1] vs. 38+/-20 mg/dL [group 2], P=0.01). End-stage renal failure (hemodialysis) was avoided by CNI-withdrawal and occurred only after CNI reduction (n=6; P=0.01). Acute rejection episodes were more common in group 2 (4 vs. 2). Graft function remained stable (echocardiography) within both groups. Adverse events were more common in group 1 (65%) than in group 2 (n=40%) and were responsible for discontinuation in 4 and 0 cases, respectively. Conversion toward a CNI-free immunosuppression (Mycophenolate, sirolimus) is superior to CNI-reduced immunosuppression in improving renal failure in late HTx-recipients. However, this benefit is relativized by the increased incidence and severity of sirolimus/MMF-associated side effects.

Aortic stiffness, kidney disease, and renal transplantation

In subjects with chronic kidney disease (CKD), treatment of high systolic blood pressure is a key element in preventing disease progression and the occurrence of cardiovascular (CV) events. This relationship between the large arterial system and kidney function was demonstrated in different renal populations. In subjects with mild to severe renal insufficiency, increased aortic stiffness and reduced creatinine clearance are closely related and are independent of traditional CV risk factors. In renal transplant patients, aortic stiffness is significantly increased irrespective of donor type. Donor age and/or acute rejection contribute independently to the increased stiffness. In the presence of renal dysfunction, an increase in systemic pulse pressure frequently may be observed and transmitted to the glomeruli. This alteration potentially initiates renal damage and favors CV events. In subjects with end-stage renal disease and high CV risk, pharmacologic modulation of the renin-angiotensin system might prevent CKD progression and CV events.

Creatinine Kinetics and the Definition of Acute Kidney Injury

Acute kidney injury (AKI) is a common and devastating medical condition, but no widely accepted definition exists. A recent classification system by the Acute Dialysis Quality Initiative (RIFLE) defines AKI largely by percentage increases in serum creatinine (SCr) over baseline. The Acute Kidney Injury Network defines the first stage by either an absolute or a percentage increase in SCr. To examine the implications of various definitions, we solved differential equations on the basis of mass balance principles. We simulated creatinine kinetics after AKI in the setting of normal baseline kidney function and stages 2, 3, and 4 chronic kidney disease (CKD). The percentage changes in SCr after severe AKI are highly dependent on baseline kidney function. Twenty-four hours after a 90% reduction in creatinine clearance, the rise in SCr was 246% with normal baseline kidney function, 174% in stage 2 CKD, 92% in stage 3 CKD, and only 47% in stage 4 CKD. By contrast, the absolute increase was nearly identical (1.8 to 2.0 mg/dl) across the spectrum of baseline kidney function. Time to reach a 50% increase in SCr was directly related to baseline kidney function: From 4 h (normal baseline) up to 27 h for stage 4 CKD. By contrast, the time to reach a 0.5-mg/dl increase in SCr was virtually identical after moderate to severe AKI (>50% reduction in creatinine clearance). We propose an alternative definition of AKI that incorporates absolute changes in SCr over a 24- to 48-h time period.

The Assessment of Residual Kidney Function After Living Donor Nephrectomy

Background The number of patients on the waiting list for kidney transplantation is increasing as a result of the cadaveric donor shortage. One way to expand the pool is living donor transplantation. However, only 2% of kidney transplants in Poland come from living-related donors. Aim We sought to assess residual renal function, incidence of hypertension, and proteinuria among living kidney donors. Patients and Methods Between 2004 and 2007, we performed 46 living donor open nephrectomies. The mean age of the kidney donor was 39 years (range, 25–57). The donors were predominantly females (61%). Mean hospitalization time was 8 days (range, 4–22). Nine donors did not report for follow-up visits. The observation periods ranged from 1 to 24 months. Physical examination, blood and urine tests, as well as ultrasound scans were performed before nephrectomy and at every follow-up visit (1, 3, 12, and 24 months post operatively). Results Mean creatinine concentration was higher at 3 months after nephrectomy than preoperatively ( P < .05). Mean creatinine clearance according to Cockroft–Gault formula and mean creatinine clearance according to abbreviated modification of diet in renal disease equation (aMDRD) decreased after donation by 30% ( P < .05). No cases of proteinuria were observed. Hypertension occurred in 1 donor (2.7%). Conclusion Living kidney donation resulted in a reduced creatinine clearance in the donor. Follow-up of living kidney donors is essential to determine risk factors for deterioration of residual kidney function.

Comparative protective effect of N‐acetyl cysteine and tetramethylpyrazine in rats with gentamicin nephrotoxicity

Gentamicin (GM) is used against serious and life-threatening infections, but its use is limited by the occurrence of nephrotoxicity, which involves the generation of free radicals. In this work we tested the effect of a compound with antioxidant properties, tertamethylpyrazine (TMP), a major constituent of the Chinese medicinal plant Lingusticum wallichi, on GM-induced nephrotoxicity, and compared it with an established anti-oxidant compound N-acetyl cysteine (NAC). Six groups of rats were studied: (1) control, treated orally (p.o.) and intraperitoneally (i.p.) with saline; (2) treated i.p. with GM (80 mg kg(-1) per day for 6 days); (3) TMP, given p.o. (100 mg kg(-1) per day for 10 days) + GM (same dose as above during the last 6 days); (4) NAC, given i.p. (500 mg kg(-1) per day for 10 days) + GM as above; (5) TMP (100 mg kg(-1) per day for 10 days) + saline; (6) NAC (500 mg kg(-1) per day for 10 days) + saline. GM nephrotoxicity was characterized by reduced creatinine clearance, increased creatinine and urea concentrations in plasma, increased urinary excretion of N-acetyl-beta-d-glucosaminidase (NAG) and total protein. These functional and structural alterations were prevented or ameliorated by NAC treatment, while TMP had only a slight mitigating effect that was less marked than that produced by NAC. The concentration of GM in the renal cortex of the rats given GM + NAC (but not TMP) was lower than that found in rats treated with GM alone by about 25%. The mechanism by which NAC and, to a lesser extent TMP, protected against GM-induced nephrotoxicity may be related, at least in part, to the decrease in oxidative stress in renal cortex.

Cyclophosphamide Remains An Important Component of Treatment in CLL Patients Receiving Pentostatin and Rituximab Based Chemoimmunotherapy

BACKGROUND: We have previously studied and reported that the combination of pentostatin (P, 2 mg/m2), cyclophosphamide (C 600 mg/m2) and rituximab (R 375 mg/m2) in previously untreated CLL is highly effective with an overall response (OR) rate of over 90% and a complete response rate (CR) of 41% (Blood 109:405–411, 2007). We also found that this regimen can be effective even in older patients (>70 y), those with elevated beta-2 microglobulin levels, and patients with mildly reduced creatinine clearances (Cancer . 109:2291–2298, 2007). To determine whether similar benefit could be achieved without inclusion of an alkylating agent, we conducted a follow-up trial testing pentostatin and rituximab without cyclophosphamide and employing a higher pentostatin dose (4 mg/m2).METHODS: Eligible pts had documentation of active CLL by standard NCI-WG criteria, and were previously untreated. Treatment schema consisted of 6 cycles of pentostatin (4 mg/m2) and rituximab given every 21 days. Pentostatin was given on the first day of each cycle following infusion of rituximab. Rituximab was given at 100mg/m2 IV at day 1, then 375 mg/m2 IV on days 3 and 5 of the first treatment cycle. During cycles 2 to 6, Rituximab was given at 375 mg/m2 as a single IV infusion day 1 of week 4, 7, 10, 13 and 16. All patients were staged two months after completion of the 6 cycles of PR using the NCI-WG criteria.PATIENT CHARACTERISTICS: Overall, 33 patients were enrolled at Mayo Clinic and Ohio State University between July 2005 and February 2008. All 33 were eligible: 82% male, median age 65 (range: 45–81), with 9 (27%) being 70 years or older. 76% had a baseline ECOG PS of 0, and the rest were ECOG PS 1. Overall, 36% of patients had intermediate Rai risk (stage I–II) and 63% high Rai risk (stage 3–4) disease. Prognostic testing revealed that 36% were CD38+, 50% were Zap-70 +, and 39% had an unmutated IgVh status. Chromosome analysis by FISH found that 99% had detectable FISH panel defect, including 61%, 27% and 3% of patients with 1, 2, or 3 FISH detects, respectively.RESULTS: 28 of 33 patients (85%) completed therapy. While on treatment, 6 pts (18%) had a dose held or modified with 4 of these delays due to hematologic AE. For adverse events deemed at least possibly related to treatment, 4 (12%) pts experienced grade 3+ hematologic toxicity and 5 (15%) experienced grade 3+ non-hematologic toxicity. Out of all 33 enrolled patients, the overall response rate was 79% with 10 CR, 6 nPR, and 10 PR. At the time of this analysis, 29/33 patients are still alive with a median follow-up time of 14 months on surviving patients. To date 17/33 (52%) of patients have progressed with an estimated median time to progression of 12 months (95% CI: 8.5–21 months). 13/26 responders have progressed. Median duration of response is 12.5 months ((95% CI: 11–21 months).Finally, since eligibility were nearly identical and enrollment accrued at the same two academic centers, we compared the patient characteristics, response rates, and PFS of the 33 patients treated with PR to the 64 patients previously treated on our PCR trial. Patients in the two studies were generally similar with respect to demographic and prognostic characteristics, although patients in the PR trial had higher WBC and were less likely to be IgVH unmutated (Table). Although the differences in ORR and CR rate were not significantly different, the PFS appeared to be inferior in patients treated with PR as compared to PCR (12 months vs. 31 months; p=0.003).CONCLUSION: Although the PR regimen achieves a high OR response rate, the PFS appears inferior to PCR therapy. These findings suggest that increasing the purine nucleoside analogue dose does not eliminate the need to include cyclophosphamide in chemoimmunotherapy for patients with CLL.PCR Trial N=64PR Trial N=33P valueAge, median(range)63 years (38–80)65 years (45–81)0.34≥70 years(%)28%27%Male77%82%0.61Rai stage 05%00.46Rai stage I–II42%36%Rai stage III–IV53%64%White Cell Count, median(range)79 × 109/L (11–519)127 × 109/L (8–430)0.04<50 × 109/L36%28%50–149 × 109/L44%25%>150 × 109/L20%47%Serum B2-microglobulin, median(range)3.97 (1.8–13.5)3.80 (2.0–8.2)0.81>2 × Upper Limit Normal(%)57%58%CD38 Positive34%36%1.00ZAP-70 Positive36%50%0.26IgVH Unmutated71%39%0.004FISHNormal,11%9%13q-35%42%+1221%24%6q-2%011q-22%18%17p-6%3%other3%3%Overall Response Rate91%79%0.12Complete Response Rate41%30%0.38Median PFS31 months12 months0.003

Iron Indices in Chronic Kidney Disease in the National Health and Nutritional Examination Survey 1988–2004

Anemia is a common and early complication of nondialysis chronic kidney disease (CKD). One contributing factor is iron deficiency, which may be particularly problematic during erythropoietin replacement therapy. The aim of this study was to examine the prevalence of iron deficiency in nondialysis CKD. The National Health and Nutritional Examination Survey (NHANES) data for NHANES III (1988 to 1994) and subsequent NHANES 2-yr datasets, 1999 to 2000, 2001 to 2002, and 2003 to 2004 were analyzed for individuals >18 yr old. It was found that low levels of iron tests [either serum ferritin < 100 ng/ml or transferrin saturation (TSAT) < 20%] were present in most patients with reduced creatinine clearance (CrCl). The percentage of low iron tests was higher among women than men, present in 57.8 to 58.8% of men and 69.9 to 72.8% of women (P < 0.001). With declining levels of CrCl, in women, TSAT levels decreased, whereas, surprisingly, serum ferritin tended to progressively increase. The percentage of anemic subjects increased progressively with declining quartiles of TSAT but was unrelated to serum ferritin quartiles. It was found that low levels of iron tests, following National Kidney Foundation/Kidney Disease Outcomes Quality Initiative guidelines (either serum ferritin < 100 ng/ml or TSAT < 20%) were present in most patients with reduced CrCl.

Predicting mortality using two renal function estimation methods in hospitalised stroke patients

The prognostic abilities of the MDRD and Cockcroft–Gault methods for estimating renal function were compared in a cohort study of 1287 patients with acute stroke admitted to a Scottish tertiary care teaching hospital. Using Cox regression analysis corrected for other prognostic variables, both the MDRD and Cockcroft–Gault equations predicted mortality independently of other prognostic factors. A 1 ml/min reduction in GFR as calculated by MDRD was associated with a 1.0% (95% CI: 0.3–1.6) increase in risk of death. A 1 ml/min reduction in creatinine clearance from the Cockcroft–Gault equation was associated with a 1.7% (95% CI: 0.9–2.6) increase in risk of death. The Cockcroft–Gault equation weakly predicted length of stay (r=0.066, p=0.02, Spearman's rank test). In conclusion, both methods independently predict early and late mortality in stroke patients, but the Cockcroft–Gault estimate has greater predictive power in this population.

Baseline renal insufficiency and risk of death among HIV-infected adults on antiretroviral therapy in Lusaka, Zambia

To examine the association between baseline renal insufficiency and mortality among adults initiating antiretroviral therapy (ART) in an urban African setting. Open cohort evaluation. We examined mortality according to baseline renal function among adults initiating ART in Lusaka, Zambia. Renal function was assessed by the Cockcroft-Gault method, the Modification of Diet in Renal Disease equation, and serum creatinine. From April 2004 to September 2007, 25 779 individuals started ART with an available creatinine measurement at baseline. When creatinine clearance was calculated by the Cockcroft-Gault method, 8456 (33.5%) had renal insufficiency: 73.5% were mild (60-89 ml/min), 23.4% moderate (30-59 ml/min), and 3.1% severe (<30 ml/min). Risk for mortality at or before 90 days was elevated for those with mildly [adjusted hazard ratio (AHR)(1/4)1.7; 95% confidence interval (95% CI)(1/4)1.5-1.9], moderately (AHR(1/4)2.3; 95% CI(1/4)2.0-2.7), and severely (AHR(1/4)4.3; 95% CI(1/4)3.1-5.5) reduced creatinine clearance. Mild (AHR(1/4)1.4; 95% CI(1/4)1.2-1.6), moderate (AHR(1/4)1.9; 95% CI(1/4)1.5-2.3), and severe (AHR(1/4)3.6; 95% CI(1/4) 2.4-5.5) insufficiency were also associated with increased mortality after 90 days, when compared with those with normal renal function. Trends were similar when renal function was estimated with Modification of Diet in Renal Disease or serum creatinine. Renal insufficiency at time of ART initiation was prevalent and associated with increased mortality risk among adults in this population. These results have particular relevance for settings like Zambia, where tenofovir--a drug with known nephrotoxicity--has been adopted as part of first-line therapy. This emphasizes the need for resource-appropriate screening algorithms for renal disease, both as part of ART eligibility and pretreatment assessment.

Infectious Diseases: Parenteral Polymyxin B Use in Patients with Multidrug-Resistant Gram-Negative Bacteremia and Urinary Tract Infections: A Retrospective Case Series

Parenteral polymyxin use declined after the 1960s, due to safety concerns. An increase in multidrug-resistant (MDR) gram-negative infections and a shortage of new agents have prompted increased use of parenteral polymyxin. To describe our clinical experience with parenteral polymyxin B for MDR gram-negative bacteremia and urinary tract infection (UTI). Paper pharmacy records were used to identify patients aged 18 years or older, presence of MDR gram-negative bacteremia or UTI, and use of parenteral polymyxin B for at least 48 hours. Electronic and paper patient records were then retrospectively reviewed. Polymyxin B susceptibility was evaluated using the Kirby-Bauer method. MDR isolates were defined as resistant to at least 3 antimicrobial classes, excluding polymyxin B. Microbiologic clearance was defined by 1 repeat urine or 2 repeat blood cultures that were sterile or growing different organisms. Secondary outcomes included hospital mortality and nephrotoxicity, defined as an increase in serum creatinine of 0.5 mg/dL or more, or a 50% reduction in creatinine clearance. Seventeen infections in 16 patients were treated with polymyxin B (1 pt. had 2 infections that were analyzed separately). Microbiologic clearance occurred in 14 of 16 (88%) cases of MDR gram-negative bacteremia or UTI in which repeat cultures were done. Ten of 16 patients died (all-cause mortality 63%). Five patients required hemodialysis prior to polymyxin B use. Six (55%) of the remaining 11 patients with baseline renal insufficiency developed nephrotoxicity, and none of them required hemodialysis. The mean +/- SD number of days from the initiation of therapy to the onset of nephrotoxicity was 7.5 +/- 2.3 (range 4-10) days. Three (50%) of 6 patients with nephrotoxicity died. Our data suggest that polymyxin B may be effective for MDR gram-negative infections in patients with limited therapeutic options, but precautions should be taken to avoid toxicity.

Application of nitric oxide and carbon monoxide in a model of renal preservation

Nitric oxide and carbon monoxide exert vasodilatory effects that minimize ischaemia-reperfusion injury. An isolated porcine kidney model was used to assess the effects of administering the nitric oxide donor sodium nitroprusside (SNP) and carbon monoxide-releasing molecule (CORM) 3 during a period of warm preservation followed by reperfusion. Kidneys were perfused under warm preservation conditions after 10 min of warm ischaemia and 16 h of cold storage in four groups: SNP, control, CORM-3 and inactive CORM-3 (inactive control). Renal function and viability were assessed. SNP and CORM-3 increased renal blood flow (RBF) during warm preservation (P = 0.014). After reperfusion, RBF was significantly improved in the CORM-3 group compared with the control group (P = 0.019). The reduction in creatinine clearance was significantly less in the CORM-3 group than in the inactive CORM-3 group (P = 0.021), and serum creatinine levels were significantly lower (P = 0.029). There was a negative correlation between RBF during warm preservation and functional parameters during reperfusion (creatinine concentration: r(s) = - 0.722, P < 0.001; sodium excretion: r(s) = - 0.912, P < 0.001). The beneficial vasodilatory effects of CORM-3 during warm preservation improved renal function during reperfusion; SNP exerted similar, although less pronounced, effects.

Determinants of Target Organ Damage in Black Hypertensive Patients Attending Primary Health Care Services in Cape Town: The Hi-Hi Study

In South Africa (SA) cardiovascular disease (CVD) is the second leading cause of death, with hypertension (HTN) being the predominant contributor to morbidity and mortality associated with this disease. We examined the prevalence and determinants of target organ damage (TOD) among urban black hypertensive South Africans attending primary health-care (PHC) services in Cape Town. Patients on HTN treatment, 35-65 years of age, participated in this cross-sectional study. Data relating to sociodemographic factors, medical history, lifestyle patterns, and HTN care regimens were obtained. Blood and urine samples were analyzed and electrocardiographs (ECGs) were recorded. Sokolow-Lyon and Minnesota Code (MC) criteria were used for identifying left ventricular hypertrophy (LVH). Reduced creatinine clearance (Cockroft-Gault), microalbuminuria, proteinuria, and elevated serum creatinine levels were used for identifying "renal impairment by any criteria" (RIC). Ischemic ECG patterns were classified in terms of MC criteria. Multivariate logistic regression analyses were carried out to identify variables independently associated with TOD. The study sample comprised 403 participants. RIC was identified in 26%, LVH in 35%, and ischemic ECG patterns in 49% of the participants. Uncontrolled HTN and an absence of diabetes were associated with LVH as per Sokolow-Lyon criteria. Older age, the presence of diabetes, and the use of beta-blockers were associated with RIC. Ischemic ECG patterns were associated with uncontrolled HTN, older age, male gender, the consumption of less alcohol, and higher levels of low-density lipoprotein cholesterol (LDL-C). TOD is common in this group of black hypertensive patients attending PHC sites. Uncontrolled HTN and older age were most often associated with TOD. Reducing the burden of TOD will require improving the quality of HTN care in PHC settings.

Erythroid response to lenalidomide (LEN) + recombinant erythropoietin (EPO) and endogenous serum EPO concentration in MDS cytokine-failures

7031 Background: LEN promotes erythropoiesis in a subset of lower risk MDS pts who fail EPO treatment (tx) [N Eng J Med 2005;352:549]. We reported that LEN acts to relieve suppression of the EPO-R signal in non-del(5q) MDS progenitors. We hypothesized that erythroid response (HI-E) to LEN is influenced by endogenous EPO level and can be augmented by combined tx (CT) with EPO in pts with low serum EPO (sEPO) concentration. To evaluate the potential benefit of CT, the effect of sEPO level, and the effects of LEN pharmacokinetics (PK) on cytopenias, we performed a two-stage PK and efficacy study. Methods: Eligible pts had transfusion-dependent (TD), Low/Int-1 IPSS MDS who failed prior treatment with EPO. In the 1st stage pts received LEN monotherapy (MT) at 10mg/d [n=25] or 15mg/d [n=15]. Single dose [n=12] and steady state [n=24] PK were evaluated on days -7 and +14 at the 10mg LEN dose. After 16 wks of MT, erythroid non-responders (NR) and minor (MiE) responders (IWG 2000) were offered CT with epoetin alpha 40,000U/wk for 8 wks. Results: Among 39 pts, median age is 72 years; 7 pts had del(5q). HI-E response to LEN-MT was 36% (n=14) [10mg, 36%; 15mg, 36%] with 13 major (Ma) [del(5q), n=6] and 1 MiE. 18 pts received CT at wk16 with 5(28%) HI-E (3Ma, 2MiE) [10mg, 10%; 15 mg, 50%]. Mean baseline sEPO was higher in HI-E responders vs. NR to LEN-MT [1177 vs.530 mU/ml], whereas in CT responders, mean wk 16 sEPO was lower [339 vs. 1116 mU/ml]. Similarly, HI-E response rate to CT was higher in pts with sEPO <500 mU/ml (4/12, 33% vs. 1/6, 17%). LEN AUC was higher in pts with reduced creatinine clearance (30–49 mL/min, n=2: 955+49; vs. >50 mL/min, n=22: 558±166). There was no difference in AUC or Cmax by magnitude of change in ANC or platelet count in the first month of tx. However, mean AUC inversely correlated with time to >50% reduction in platelet count (ANOVA, P = 0.04). Conclusions: These data suggest that HI-E response to LEN in TD-cytokine failures is sEPO-dependent, yielding a higher response rate to LEN-MT in pts with appropriate sEPO elevation, whereas addition of EPO may improve response in pts with low EPO production. The benefit of CT with LEN+EPO will be investigated in a phase III intergroup study (E2905) in pts who failed primary EPO tx or have a poor cytokine response profile. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Celgene Celgene, Pharmion Celgene Pharmion

Global risk stratification in primary hypertension: the role of the kidney

Microalbuminuria and a reduction in creatinine clearance are well known, independent predictors of unfavourable cardiovascular prognosis. Our aim was to evaluate the impact of renal damage on global risk stratification in 459 non-diabetic, untreated hypertensive patients (64% men, mean age 47.3 years). Renal damage was defined as creatinine clearance < 60 ml/min per 1.73 m2 (Cockcroft-Gault formula) or the presence of microalbuminuria (albumin to creatinine ratio). Cardiac and vascular organ damage was assessed by ultrasound scan. We evaluated the impact of renal damage, left ventricular hypertrophy and carotid atherosclerosis on risk stratification as recommended by the 2007 European Society of Hypertension-European Society of Cardiology Guidelines. The prevalence of renal damage, microalbuminuria and creatinine clearance < 60 ml/min per 1.73 m2 was 24, 12 and 13%, respectively. There was no correlation between albuminuria and estimated creatinine clearance, and only 0.9% of patients showed microalbuminuria and reduced creatinine clearance simultaneously. The presence of renal damage entailed a 3.3 times higher risk of having cardiovascular abnormalities. Based on routine work-up, 58% of our study patients were classified as high-very high risk. The simultaneous evaluation of albuminuria and creatinine clearance resulted in a significant change in risk stratification, since 68% of patients were classified in the high-very high risk class. The search for left ventricular hypertrophy or carotid atherosclerosis by ultrasonography did not improve risk stratification significantly as compared to the assessment of renal damage. Our findings support the assessment of renal abnormalities as the first step when evaluating target organ damage for cardiovascular risk assessment in hypertensive patients.

Effect of CLA isomers on renal injury in the obese fa/fa Zucker rat

Obesity is associated with greater risk and incidence of nephropathy. Mixed conjugated linoleic acid (CLA) isomers have beneficial effects on renal disease, but the effect of individual CLA isomers is not known. Our objective was to test whether dietary CLA isomers would alter renal injury progression in the obese fa/fa Zucker rat. Male obese and lean 17 wk old fa/fa Zucker rats were given diets with either 0.4% c9, t11 CLA, 0.4% t10, c12 CLA or control diet for 8 wk, after which renal function and histology were assessed. The dietary t10, c12 CLA decreased the glomerular volume, worsened the glomerulosclerosis and increased macrophage infiltration compared with control. In the t10, c12 CLA group, there was a trend for increased kidney weight, proteinuria, kidney fibrosis and tubular injury (tubular atrophy, calcification and casts) and reduced creatinine clearance, but these were not statistically different from control. The dietary c9, t11 CLA group had smaller glomeruli than control, and less glomerulosclerosis, fibrosis and macrophage infiltration compared with the t10, c12 CLA group. Hence, t10, c12 CLA exacerbates renal injury associated with obesity, while c9, t11 CLA does not, and may be protective. (Supported by Manitoba Agriculture Food and Rural Development Initiative, Dairy Farmers of Canada and NSERC)

Disturbance of lymph circulation develops renal fibrosis in rats with or without contralateral nephrectomy

The knowledge on renal lymphatics is very limited and their importance is often neglected in kidney transplantation surgery practice. Early papers demonstrated that acute ligation of hilar lymphatic ducts has a significant effect on sodium excretion and urine volume. However, the long-term effects of hilar lymphatic ducts ligation on renal function and histology were not mentioned. Here we show the time course of renal lesions caused by long-term ligation of renal hilar lymphatic vessels in rats with or without contralateral nephrectomy. Animals were divided into three groups: rats with bilateral renal lymphatic ducts ligation (2KL); rats with one renal ligation and another nephrectomy (1KL); sham-operated rats (Sham). Proteinuria, serum creatinine value and creatinine clearance were monitored. Renal histology was examed by light microscopy. Further biochemical analysis was provided using real-time polymerase chain reaction, immunostaining and western blot techniques. From week 1 after ligation, both 1KL and 2KL rats developed severe proteinuria, whereas elevated serum creatinine and reduced creatinine clearance were observed from week 2. Histomorphological changes appeared in ligated kidneys at week 2, characterized by tubular damage, tubulointerstitial fibrosis and expansion of the mesangium. Overexpression of transforming growth factor-beta1 (TGF-beta1), Smad2/3, COL I genes and proteins were detected in 1KL and 2KL rats. Compared with 2KL rats, the changes in renal function and histology were more pronounced in 1KL rats. Disturbance of lymph circulation induced chronic renal failure and renal fibrosis, which were aggravated by lymphatic vessels ligation combined with contralateral nephrectomy. The effect of lymphatic ducts ligation on renal lesions may be explained by enhanced activation of the TGF-beta1/Smad signalling.