Deferral of Estimated Glomerular Filtration Rate Testing Before Contrast-Enhanced CT in Low-Risk Emergency Department Patients: Assessment of Safety and Impact on Throughput.

OBJECTIVE: To assess the safety and utility of deferring estimated glomerular filtration rate (eGFR) testing before contrast-enhanced CT (CECT) in low-risk emergency department (ED) patients. METHODS: A new question was added to CECT order screens, allowing ordering ED providers to defer eGFR testing in patients deemed low risk for contrast-induced acute kidney injury (AKI). Low risk was defined as no known chronic kidney disease (CKD) or risk factors for AKI or CKD. Patients on chronic dialysis were deemed low risk. The project included three phases: baseline, pilot (optional order question), and full implementation (required order question). Outcomes were operational throughput metrics of CECT order to protocol (O to P) and order to begin (O to B) times. As a balancing safety measure, the proportion of patients deemed to be "low risk" and subsequently found to have eGFR value less than 30 mL/min/1.73 m2 was reported. RESULTS: A total of 16,446 CECT studies were included from four EDs. In the pilot phase, provider engagement rates with the question were low (5%-14%). After full implementation, median O to P time improved from 23.93 min at baseline to 13.02 (P < .0001) and median O to B time improved from 80.34 min to 76.48 (P = .0002). In 0.3% (2 of 646) studies, CECT was completed in patients categorized as low risk by the ED provider with subsequently resulted eGFR <30 mL/min/1.73 m2. DISCUSSION: Upfront clinical risk assessment for AKI and CKD by ED providers can be used to safely defer eGFR testing and improve operational performance for patients requiring CECT.

Comparative Safety and Effectiveness of Warfarin or Rivaroxaban Versus Apixaban in Patients With Advanced CKD and Atrial Fibrillation: Nationwide US Cohort Study.

RATIONALE & OBJECTIVE: Head-to-head data comparing the effectiveness and safety of oral anticoagulants in patients with atrial fibrillation (AF) and advanced chronic kidney disease (CKD) are lacking. We compared the safety and effectiveness of warfarin or rivaroxaban versus apixaban in patients with AF and non-dialysis-dependent CKD stage 4/5. STUDY DESIGN: Propensity score-matched cohort study. SETTING & PARTICIPANTS: 2 nationwide US claims databases, Medicare and Optum's deidentified Clinformatics Data Mart Database, were searched for the interval from January 1, 2013, through March 31, 2022, for patients with nonvalvular AF and CKD stage 4/5 who initiated warfarin versus apixaban (matched cohort, n=12,488) and rivaroxaban versus apixaban (matched cohort, n = 5,720). EXPOSURES: Warfarin, rivaroxaban, or apixaban. OUTCOMES: Primary outcomes included major bleeding and ischemic stroke. Secondary outcomes included all-cause mortality, major gastrointestinal bleeding, and intracranial bleeding. ANALYTICAL APPROACH: Cox regression was used to estimate HRs, and 1:1 propensity-score matching was used to adjust for 80 potential confounders. RESULTS: Compared with apixaban, warfarin initiation was associated with a higher rate of major bleeding (HR, 1.85; 95% CI, 1.59-2.15), including major gastrointestinal bleeding (1.86; 1.53-2.25) and intracranial bleeding (2.15; 1.42-3.25). Compared with apixaban, rivaroxaban was also associated with a higher rate of major bleeding (1.69; 1.33-2.15). All-cause mortality was similar for warfarin (1.08; 0.98-1.18) and rivaroxaban (0.94; 0.81-1.10) versus apixaban. Furthermore, no statistically significant differences for ischemic stroke were observed for warfarin (1.14; 0.83-1.57) or rivaroxaban (0.71; 0.40-1.24) versus apixaban, but the CIs were wide. Similar results were observed for warfarin versus apixaban in the positive control cohort of patients with CKD stage 3, consistent with randomized trial findings. LIMITATIONS: Few ischemic stroke events, potential residual confounding. CONCLUSIONS: In patients with AF and advanced CKD, rivaroxaban and warfarin were associated with higher rates of major bleeding compared with apixaban, suggesting a superior safety profile for apixaban in this high-risk population. PLAIN-LANGUAGE SUMMARY: Different anticoagulants have been shown to reduce the risk of stroke in patients with atrial fibrillation, such as warfarin and direct oral anticoagulants like apixaban and rivaroxaban. Unfortunately, the large-scale randomized trials that compared direct anticoagulants versus warfarin excluded patients with advanced chronic kidney disease. Therefore, the comparative safety and effectiveness of warfarin, apixaban, and rivaroxaban are uncertain in this population. In this study, we used administrative claims data from the United States to answer this question. We found that warfarin and rivaroxaban were associated with increased risks of major bleeding compared with apixaban. There were few stroke events, with no major differences among the 3 drugs in the risk of stroke. In conclusion, this study suggests that apixaban has a better safety profile than warfarin and rivaroxaban.

Harmful effect of repetitive intravenous iodinated contrast media administration on the long-term renal function of patients with early gastric cancer.

This retrospective study investigated whether repetitive exposure to intravenous iodinated contrast media (ICM) affects long-term renal function in patients who undergo curative surgery for early gastric cancer (EGC) collected from the Korean Health Insurance and Review Assessment (HIRA) database. Patients diagnosed with gastric cancer between January 2010 and December 2013 underwent regular computed tomography (CT) scans to monitor for extragastric recurrence. Patients who already had chronic kidney disease (CKD) before cancer diagnosis or had undergone chemotherapy or repeated surgery were excluded. A nested case-control study design was chosen to analyze the effect of repetitive ICM exposure to long-term renal function by comparing patients who developed CKD 2 years after cancer diagnosis and patients who did not. Among 59,971 patients collected according to inclusion and exclusion criteria, 1021 were diagnosed with CKD 2 years after cancer diagnosis. Using 1:5 matching after adjusting for age, sex and date of cancer diagnosis, 5097 control patients were matched to 1021 CKD patients. Conditional logistic regression showed that the number of CTs taken using ICM slightly increased the odds of CKD (odds ratio, 1.080; 95% confidence interval (CI): 1.059, 1.100; P < 0.0001). Thus, the administration of ICM might contribute to chronic renal function impairment.

Disease burden of chronic kidney disease attributable to lead exposure: A global analysis of 30 years since 1990.

BACKGROUND: Exposure to lead (Pb) is associated with an increased risk of chronic kidney disease (CKD). However, limited studies explored the global burden of CKD attributable to Pb exposure, especially in countries with different development levels. This study aimed to comprehensively evaluate the temporal and spatial trend in the disease burden of CKD attributable to Pb exposure in 204 countries and territories from 1990 to 2019. METHODS: We used the data from Global Burden of Disease Study (GBD) 2019 to estimate annual deaths, disability-adjusted life years (DALYs), age-standardized mortality rates (ASMR), and age-standardized DALYs rate (ASDR) of CKD attributable to Pb exposure. The annual average percentage change (AAPCs) was calculated using the Joinpoint model to evaluate the changing trend of CKD ASMR and ASDR attributable to Pb exposure from 1990 to 2019. Meanwhile, age-period-cohort (APC) model was used to assess changes in the mortality of CKD attributable to Pb exposure from 1990 to 2019. RESULTS: Global ASMR for CKD attributable to Pb exposure trended upward from 1990 to 2019. ASMR and ASDR were the highest in low and low-middle SDI regions. With the APC model, we found that global mortality rates for CKD attributable to Pb exposure increased with age. The global period rate ratio showed the highest value in 2000-2004 and the lowest in 2015-2019, while the global cohort rate ratio showed the highest value in 1941-1949 and the lowest during 1986-1994. CONCLUSIONS: From 1990 to 2019, the global burden of CKD attributable to Pb exposure increased globally, especially in low and low-middle SDI regions, as well as the elderly. Pb exposure is still a great threat to the global burden of CKD, and the implementation of effective prevention measures to reduce Pb exposure in the environment should be continually strengthened.

Efficacy and safety assessment of mineralocorticoid receptor antagonists in patients with chronic kidney disease.

BACKGROUND: The objective of our study is to evaluate the efficacy and safety of mineralocorticoid receptor antagonists (MRAs) and determine the optimal MRA treatment regimen in patients with chronic kidney disease (CKD). METHODS: We searched PubMed, Embase, Web of Science, and the Cochrane Library from their inception to June 20, 2022. The composite kidney outcome, cardiovascular events, urinary albumin to creatinine ratio (UACR), estimated glomerular filtration rate (EGFR), serum potassium, systolic blood pressure (SBP), diastolic blood pressure (DBP), creatine and creatine clearance were included for analysis. We conducted pairwise meta-analyses and Bayesian network meta-analyses (NMA) and calculated the surface under the cumulative ranking curve (SUCRA). RESULTS: We included 26 studies with 15,531 participants. By pairwise meta-analyses, we found that MRA treatment could significantly reduce UACR in CKD patients with or without diabetes. Notably, compared to placebo, Finerenone was associated with a lower risk of composite kidney outcome and cardiovascular events. Data from NMA demonstrated an overt UACR reduction without increasing serum potassium by Apararenone, Esaxerenone, and Finerenone in CKD patients. Spironolactone decreased SBP and DBP but elevated CKD patients' serum potassium. CONCLUSIONS: Compared to placebo, Apararenone, Esaxerenone, and Finerenone might ameliorate albuminuria in CKD patients without causing elevated serum potassium levels. Remarkably, Finerenone conferred a cardiovascular benefit, and Spironolactone lowered blood pressure in CKD patients.

Cost-Effectiveness of Dapagliflozin as a Treatment for Chronic Kidney Disease: A Health-Economic Analysis of DAPA-CKD.

BACKGROUND AND OBJECTIVES: CKD imposes a significant burden on patients and health care providers, particularly upon reaching kidney failure when patients may require KRT. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial demonstrated that dapagliflozin, with standard therapy, reduced CKD progression and KRT requirement. The study objective was to estimate the cost-effectiveness of dapagliflozin for the treatment of CKD from payer perspectives in the United Kingdom, Germany, and Spain. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We constructed a lifetime Markov model to characterize outcomes in patients with CKD on the basis of the DAPA-CKD trial. Health states were defined by eGFR level and KRT type. Direct health care costs and utility values were sourced from published literature and the DAPA-CKD trial, respectively. Costs and benefits were discounted at 3.5% per annum in the United Kingdom and 3% in Germany and Spain. RESULTS: In patients eligible for the DAPA-CKD trial, treatment with dapagliflozin was predicted to reduce rates of CKD progression, with patients predicted to spend 1.7 (95% credibility interval, 0.8 to 2.4) more years in the eGFR range 15-89 ml/min per 1.73 m2 versus standard therapy alone (12.1; 95% credibility interval, 8.9 to 14.1 versus 10.4; 95% credibility interval, 7.7 to 12.4 years). Life expectancy (undiscounted) was correspondingly predicted to increase by 1.7 (95% credibility interval, 0.7 to 2.5) years (15.5; 95% credibility interval, 11.1 to 18.2 versus 13.8; 95% credibility interval, 9.9 to 16.5 years). This in addition to reduced incidence of adverse clinical outcomes, including hospitalization for heart failure, resulted in modeled quality-adjusted life year (discounted) gains between 0.82 (95% credibility interval, 0.38 to 1.18) and 1.00 (95% credibility interval, 0.46 to 1.41). These gains translated to incremental cost-effectiveness ratios of $8280, $17,623, and $11,687 in the United Kingdom, Germany, and Spain, respectively, indicating cost-effectiveness at willingness-to-pay thresholds (United Kingdom: $27,510 per quality-adjusted life year; Germany and Spain: $35,503 per quality-adjusted life year). CONCLUSIONS: In patients meeting the eligibility requirements for the DAPA-CKD trial, dapagliflozin is likely to be a cost-effective treatment within the UK, German, and Spanish health care systems. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD), NCT03036150.

Incidence, Pathogenesis, and Management of Proton Pump Inhibitor-Induced Nephrotoxicity.

Proton pump inhibitors are widely used in the treatment of various acid-related diseases and are among the most commonly used drugs. Studies estimate that 25-70% of proton pump inhibitors are prescribed for inappropriate treatments, doses, and indications, where the benefits of proton pump inhibitor use may be less than the risk of adverse drug reactions for many patients. Acute interstitial nephritis is an immune-mediated atypical kidney injury in the long-term use of proton pump inhibitors that causes problems for clinicians and patients. In this review, we summarize the current knowledge of proton pump inhibitors inducing acute interstitial nephritis, chronic kidney disease, and even end-stage renal disease in terms of incidence, pathogenesis, factors, clinical features, and diagnosis. We discuss how these factors change under conditions of acute interstitial nephritis, chronic kidney disease, and end-stage renal disease. The purpose of this review is to assess the current evidence to help clinicians and patients interpret the potential causal relationship between proton pump inhibitor intake and nephrotoxicity. This prompts clinicians to consider the appropriate dose and duration of proton pump inhibitor therapy to avoid inappropriate use.

Exposure Assessment of Fluoride Intake Through Commercially Available Black Tea (Camellia sinensis L.) from Areas with High Incidences of Chronic Kidney Disease with Undetermined Origin (CKDu) in Sri Lanka.

Fluoride is a beneficial trace element for human health as its deficiency and excess levels can cause detrimental health effects. In Sri Lanka, dry zone regions can have excessive levels of fluoride in drinking water and can cause dental and skeletal fluorosis. In addition to drinking water, traditional habits of tea consumption can cause an additional intake of fluoride in the population. A total number of 39 locally blended black tea samples were collected from a village where chronic kidney disease with undetermined origin (CKDu) is prevalent. In addition, unblended tea samples were obtained from tea-producing factories. The fluoride contents in infusions of 2% weight per volume (w/v) were measured using calibrated ion-selective fluoride electrodes. The mean fluoride content was 2.68±1.03 mg/L in loose tea, 1.87±0.57mg/L in packed tea samples, and 1.14±0.55 mg/L in unblended tea. Repeated brewing of the same tea leaves showed that over 50% of fluoride leached into the solution in the first infusion. An estimate of the daily total average fluoride intake via tea consumption per person is 2.68 mg per day. With groundwater in many dry zone regions in Sri Lanka showing high fluoride levels that exceed 0.5 mg/L, the additional daily intake can rapidly exceed recommended thresholds of 2 mg/day. This can add to adverse health impacts that might also relate to CKDu.

A Review of Specific Biomarkers of Chronic Renal Injury and Their Potential Application in Nonclinical Safety Assessment Studies.

A host of novel renal biomarkers have been developed over the past few decades which have enhanced monitoring of renal disease and drug-induced kidney injury in both preclinical studies and in humans. Since chronic kidney disease (CKD) and acute kidney injury (AKI) share similar underlying mechanisms and the tubulointerstitial compartment has a functional role in the progression of CKD, urinary biomarkers of AKI may provide predictive information in chronic renal disease. Numerous studies have explored whether the recent AKI biomarkers could improve upon the standard clinical biomarkers, estimated glomerular filtration rate (eGFR), and urinary albumin to creatinine ratio, for predicting outcomes in CKD patients. This review is an introduction to alternative assays that can be utilized in chronic (>3 months duration) nonclinical safety studies to provide information on renal dysfunction and to demonstrate specific situations where these assays could be utilized in nonclinical drug development. Novel biomarkers such as symmetrical dimethyl arginine, dickkopf homolog 3, and cystatin C predict chronic renal injury in animals, act as surrogates for GFR, and may predict changes in GFR in patients over time, ultimately providing a bridge from preclinical to clinical renal monitoring.

Assessment of chronic renal injury in patients with chronic myeloid leukemia in the chronic phase receiving tyrosine kinase inhibitors.

We aimed to evaluate the incidence of chronic renal injury in patients with chronic myeloid leukemia in the chronic phase (CML-CP) receiving tyrosine kinase inhibitors (TKIs) and to identify the associated factors. Data for CML-CP patients with normal estimated glomerular filtration rate (eGFR) at baseline and receiving TKI therapy ≥ 3 months were retrospectively reviewed. The CRAE (chronic renal adverse event, defined as a 30% eGFR reduction from baseline or eGFR < 60 ml/min/1.73 m2 ≥ 90 days whichever occurred first)-free survival rates at 3 years in the imatinib cohort (n = 360) were significantly lower than those in the nilotinib cohort (n = 100) (55% versus 77%, P = 0.001) as a first-line TKI therapy. In multivariate analyses, imatinib, male sex, increasing age, and previous non-TKI treatment were associated with poor CRAE-free survival. In newly diagnosed patients who received imatinib treatment (n = 40), 24-h urine protein levels significantly increased after 6 months, and urinary ß2-microglobulin values significantly increased compared to those in the nilotinib cohort (n =15) at 36 months (P = 0.042) and 42 months (P = 0.039). There was no significant difference in CRAE-free survival rates at 3 years between the nilotinib (n = 65) and dasatinib (n = 74) cohorts (67% versus 83%, P = 0.832) as second- or third-line TKI therapies. In multivariate analyses, previous non-TKI treatment was associated with poor CRAE-free survival. We concluded that imatinib was significantly correlated to chronic renal injury, possibly associated with glomerulus and renal tubular injury, compared with nilotinib as a first-line TKI therapy in CML-CP patients. However, nilotinib and dasatinib had similar mild adverse impacts on renal function as second- or third-line therapies.

Kidney Safety Assessment: Current Practices in Drug Development.

The kidney's role as a major route of metabolism and clearance of xenobiotics and its ability to concentrate the glomerular filtrate make it particularly vulnerable to drug-induced toxicity. Improving kidney safety is an active area of research and there is a need in early stages of drug development for strategies and model systems to reliably identify nephrotoxic compounds and sufficiently characterize mechanisms to support drug pipeline decision making. In later stages of drug development the value of sensitive translational biomarkers to monitor kidney toxicity across species in nonclinical and clinical settings is gaining realization. Various tools and strategies for kidney safety assessment have emerged over the past decade; however, there is currently no clear consensus on best practices for their use across different phases of drug development. Here, we provide perspective on the scope of this problem in drug development, and an overview of progress in the field of kidney safety including several informative case examples of kidney toxicity de-risking scenarios encountered in the pharmaceutical industry. The results of a survey of pharmaceutical companies conducted through the Innovation and Quality Drug Safety consortium provides additional insight into recent experiences with compound attrition and different de-risking approaches across the industry.

Sixteen years of creatinine measurements among 460 000 individuals-The Funen Laboratory Cohort (FLaC), a population-based pharmacoepidemiological resource to study drug-induced kidney disease.

Register-based administrative data comprise the backbone of pharmacoepidemiological research. However, information from these registers lacks biochemical details. The aim of our study was to describe the creation, coverage and content of the Funen Laboratory Cohort (FLaC). FLaC is a database comprising all inhabitants of Funen, Denmark, who in the study period of January 2000 to December 2015 had their creatinine levels measured. Data were linked to the Danish nationwide registers with information on vital status, redeemed prescriptions, discharge diagnoses, and socio-economic status. A total of 693 843 individuals lived on Funen during the study period, and we included 460 365 (66.4%) individuals with a creatinine measurement. In total, 7 742 124 creatinine measurements were performed during the study period. The coverage increased with increasing age, reaching 90%-100% of all 65-90 + year-olds in 2015. We found that an overall coverage of individuals recorded in FLaC with at least one creatinine measured redeeming prescriptions from public pharmacies was 83% (interquartile range [IQR] 75%-89%) compared to the entire Funen population. In total, 94.1% of all individuals with a discharge diagnosis of chronic kidney disease (CKD) were covered in FLaC, but only 16.5% (n = 3136) of all individuals with a laboratory-confirmed CKD also had a discharge diagnosis of CKD. We described the creation and content of the FLaC - a haven and a valuable resource for pharmacoepidemiological research using Danish nationwide administrative registers enriched with individual-level biochemical information in a population-based setting.

The case for cautious consumption: NSAIDs in chronic kidney disease.

PURPOSE OF REVIEW: Strong epidemiological and pathologic evidence associates NSAIDs with kidney disease, both acute and chronic. Hence, the usage of NSAIDs has decreased in patients with, or at risk for, chronic kidney disease (CKD). Coupled with this has been a rise in use of opioids and other non-NSAID alternatives, which do come with significant, and underrecognized, risk of nonrenal adverse events. We review the literature to understand if this shift is appropriate or deleterious. RECENT FINDINGS: NSAIDs do have a low but tangible risk in causing acute kidney injury, electrolyte imbalances, and increasing blood pressure. However, their role in causing progressive kidney disease is due to long-term usage in high cumulative dosages, and the use of NSAIDs in combination with other agents. Alternatives such as opioids, tramadol, gabapentin and baclofen have weak evidence to support their use and strong evidence to show their harm in patients with CKD. SUMMARY: Tradeoffs are inherent in using active pharmaceuticals, and NSAIDs are no exception. Balancing potential benefits with possible adverse effects around pain management should be a part of every conversation for patients with kidney disease.

A quick scoping review of efficacy, safety, economic, and health-related quality-of-life outcomes of short- and long-acting erythropoiesis-stimulating agents in the treatment of chemotherapy-induced anemia and chronic kidney disease anemia.

Erythropoiesis-stimulating agents (ESAs) are man-made forms of erythropoietin used in the treatment of anemia. This quick-scoping review of systematic literature reviews (SLRs) was conducted to define the clinical, economic, and health-related quality of life (HRQoL) outcomes for short-acting and long-acting ESAs in patients with chronic kidney disease-induced anemia (CKD-IA) and patients with chemotherapy-induced anemia (CIA). Embase, Medline, and the Cochrane Database of Systematic Reviews were searched from their establishment until October 2017. SLRs related to the use of short-acting and long-acting ESAs in the treatment of CIA and CKD-IA were included. Forty-eight studies met the inclusion criteria. The evidence suggests little difference in efficacy, HRQoL, and safety outcomes among ESA types. Cost-effectiveness and market price are likely to become determining factors driving the choice of agent. Comparative studies and costing models accounting for the utilization of biosimilars are needed to establish which ESAs are more cost-effective.

Assessment of chronic renal injury from melamine-associated pediatric urolithiasis: an eighteen-month prospective cohort study.

BACKGROUND: The illegal use of melamine in powdered baby formula resulted in a widespread outbreak of melamine-associated pediatric urolithiasis and kidney damage in China in 2008. We conducted this study because more needs to be known about the long-term effects of melamine-associated urolithiasis and kidney damage. OBJECTIVES: To determine the prognosis and long-term implications of chronic kidney damage in children with urolithiasis resulting from melamine consumption. DESIGN: Prospective cohort study. SETTING: Children's Hospital of Fudan University. PATIENTS AND METHODS: Children six years of age or older with a history of having consumed melamine-contaminated milk powder were voluntarily screened. We measured urinary microprotein profiles [microalbumin (ALBU), immunoglobulin G (IgG), and n-acetyl-ß-d-glucosidase (NAG)] and creatinine (CR) results at 6 and 18 months in children with melamine-associated urolithiasis. This study was conducted from September 17 to October 15, 2008. MAIN OUTCOME MEASURES: Changes in urinary microprotein profiles. RESULTS: Of 8335 children screened, 102 children (1.22%) were diagnosed with melamine-associated urolithiasis. Follow-up rates at 6 and 18 months were 91.4% (96/105) and 89.2% (91/102), respectively. Eighteen months later, 90.3% patients had spontaneously passed a stone. The incidence rates of proteinuria and microscopic hematuria at 6 months were significantly higher than at 18 months (P=.029 and P=.017, respectively). The proportion of patients with abnormal ALBU/CR, IgG/CR and NAG/CR at 6 months (27.6%, 17.1% and 21.1%, respectively) was significantly higher than at 18 months (6.4%, 5.1% and 12.8%, respectively). The high concentration of melamine consumed was the primary factor correlated with the high microprotein levels. Approximately 90% melamine-associated urolithiasis cases can be resolved within 18 months by non-surgical therapy. CONCLUSION: The long-term presence of stones associated with a previous exposure to melanine can cause chronic kidney glomerular and tubular injuries. Passing these stones as soon as possible can reduce kidney injury and accelerate recovery. LIMITATIONS: We could not control for possible selection bias due to more visits to our hospital or visits to our hospital after diagnosis at other hospitals, which might have increased the rate of diagnosis.

Environmental exposures, socioeconomics, disparities, and the kidneys.

Kidney disease disproportionately affects racial and ethnic minority populations, the poor, and the socially disadvantaged. The excess risk of kidney disease among minority and disadvantaged populations can only be partially explained by an excess of diabetes, hypertension, and poor access to preventive care. Disparities in the environmental exposure to nephrotoxicants have been documented in minority and disadvantaged populations and may explain some of the excess risk of kidney disease. High-level environmental and occupational exposure to lead, cadmium, and mercury are known to cause specific nephropathies. However, there is growing evidence that low-level exposures to heavy metals may contribute to the development of CKD and its progression. In this article, we summarize the excess risk of environmental exposures among minority and disadvantaged populations. We also review the epidemiologic and clinical data linking low-level environmental exposure to lead, cadmium, and mercury to CKD and its progression. Finally, we briefly describe Mesoamerican nephropathy, an epidemic of CKD affecting young men in Central America, which may have occupational and environmental exposures contributing to its development.

Pharmacokinetic-pharmacodynamic target attainment analyses to evaluate in vitro susceptibility test interpretive criteria for ceftaroline against Staphylococcus aureus and Streptococcus pneumoniae.

To provide support for in vitro susceptibility test interpretive criteria decisions for ceftaroline against Staphylococcus aureus and Streptococcus pneumoniae, as well as dose adjustment recommendations for renal impairment, pharmacokinetic-pharmacodynamic (PK-PD) target attainment was evaluated for simulated patients administered intravenous (i.v.) ceftaroline fosamil at 600 mg twice daily (q12h) and simulated patients with renal impairment administered various dosing regimens. Using a previously developed population PK model, Monte Carlo simulation was used to generate ceftaroline plasma concentration profiles for simulated patients with normal renal function or mild, moderate, or severe renal impairment. Using these profiles, the percentage of time during the dosing interval that free-drug concentrations remained above the MIC (f%T>MIC) for ceftaroline at steady state was calculated. Percentages of simulated patients achieving f %T>MIC targets for S. aureus and S. pneumoniae based on murine infection models were calculated by MIC. At MICs of 2 mg/liter for S. aureus and 1 mg/liter for S. pneumoniae, the percentages of simulated patients with normal renal function and mild renal impairment following administration of ceftaroline fosamil at 600 mg q12h, moderate renal impairment following administration of ceftaroline fosamil at 400 mg q12h, and severe renal impairment following administration of ceftaroline fosamil at 300 mg q12h achieving f %T>MIC targets (≥26 for S. aureus and ≥44 for S. pneumoniae) exceeded 90%. The results of these analyses, which suggested that in vitro susceptibility test interpretive criteria defining susceptible could be as high as MICs of ≤2 and ≤1 mg/liter for ceftaroline against S. aureus and S. pneumoniae, respectively, provide support for current FDA and CLSI criteria, which define susceptible as MICs of 1 and 0.5 mg/liter, respectively. Recommendations for dose adjustments for patients with renal impairment were also supported by the results of these analyses.

Assessment and management of renal impairment in chemotherapy for urogenital cancer.

The method of diagnosing chronic kidney disease by simple estimated glomerular filtration rate equations has demonstrated a high prevalence of chronic kidney disease among the genitourinary cancer patients. Approximately 30-50% of urothelial cancer patients have Grade 3 chronic kidney disease before chemotherapy, and the rate increases to around 80% in upper urinary tract cancer patients who have undergone radical surgery. Several gold-standard treatments, including cisplatin for urothelial/testicular tumors and anti-vascular endothelial growth factor therapy for kidney cancers, are known to be associated with the development of renal impairment. However, which renal function assessments are best to select a chemotherapy regimen remain unknown. Most testicular tumor patients are cured by intensive combined chemotherapy with cisplatin, but chemotherapy can induce chronic kidney disease in testicular cancer survivors. The prevalence of Stage 3 chronic kidney disease among the testicular cancer survivors is between 10 and 20%. Thus, the estimated glomerular filtration rate assessment is a useful tool for monitoring the development of chronic kidney disease among the cancer survivors, and assessment of renal function is mandatory before the treatment of these genitourinary cancer patients.

Cadmium risk assessment in relation to background risk of chronic kidney disease.

Cadmium's noncancer effects on the kidney represent a useful case study of the unified approach to toxicity assessment described in a recent National Academy of Science report. Cadmium (Cd) is recognized to exert toxic effects on the kidney at low dose without a demonstrable threshold. The implications of current dietary exposure and regulatory limits can be understood in terms of risk for chronic kidney disease (CKD) since both Cd adverse effects and CKD are defined by the same continous parameter (loss in glomerular filtration rate [GFR]). The Cd dose response on GFR derived from a study of Swedish women was applied to the baseline population distribution of GFR to determine the effect of Cd on CKD risk. The baseline population of 47.8-yr-old women was estimated to carry a 10% rate of Stage 3 CKD, similar to national statistics in the United States. A chronic daily dose of Cd at 1 µg/kg/d produced a left shift in this distribution and increased the population risk of CKD by an estimated 25%. A 10-fold lower Cd dose was associated with an increase in population risk of 2.7%, and this rose to 3.4% in 75-yr-olds. These estimates (1) provide additional perspective to the traditional risk/no risk approaches used in setting U.S. Environmental Protection Agency (EPA) reference doses (RfD) and Agency for Toxic Substances and Disease Registry (ATSDR) minimum risk levels (MRL) and (2) demonstrate the utility of considering chemical additivity to background disease in assessing human risk.