Use of Estimating Equations for Dosing Antimicrobials in Patients with Acute Kidney Injury Not Receiving Renal Replacement Therapy.

Acute kidney injury (AKI) can potentially lead to the accumulation of antimicrobial drugs with significant renal clearance. Drug dosing adjustments are commonly made using the Cockcroft-Gault estimate of creatinine clearance (CLcr). The Modified Jelliffe equation is significantly better at estimating kidney function than the Cockcroft-Gault equation in the setting of AKI. The objective of this study is to assess the degree of antimicrobial dosing discordance using different glomerular filtration rate (GFR) estimating equations. This is a retrospective evaluation of antimicrobial dosing using different estimating equations for kidney function in AKI and comparison to Cockcroft-Gault estimation as a reference. Considering the Cockcroft-Gault estimate as the criterion standard, antimicrobials were appropriately adjusted at most 80.7% of the time. On average, kidney function changed by 30 mL/min over the course of an AKI episode. The median clearance at the peak serum creatinine was 27.4 (9.3⁻66.3) mL/min for Cockcroft Gault, 19.8 (9.8⁻47.0) mL/min/1.73 m² for MDRD and 20.5 (4.9⁻49.6) mL/min for the Modified Jelliffe equations. The discordance rate for antimicrobial dosing ranged from a minimum of 8.6% to a maximum of 16.4%. In the event of discordance, the dose administered was supra-therapeutic 100% of the time using the Modified Jelliffe equation. Use of estimating equations other than the Cockcroft Gault equation may significantly alter dosing of antimicrobials in AKI

Phenotype standardization for drug-induced kidney disease.

Drug-induced kidney disease is a frequent cause of renal dysfunction; however, there are no standards to identify and characterize the spectrum of these disorders. We convened a panel of international, adult and pediatric, nephrologists and pharmacists to develop standardized phenotypes for drug-induced kidney disease as part of the phenotype standardization project initiated by the International Serious Adverse Events Consortium. We propose four phenotypes of drug-induced kidney disease based on clinical presentation: acute kidney injury, glomerular, tubular, and nephrolithiasis, along with the primary and secondary clinical criteria to support the phenotype definition, and a time course based on the KDIGO/AKIN definitions of acute kidney injury, acute kidney disease, and chronic kidney disease. Establishing causality in drug-induced kidney disease is challenging and requires knowledge of the biological plausibility for the specific drug, mechanism of injury, time course, and assessment of competing risk factors. These phenotypes provide a consistent framework for clinicians, investigators, industry, and regulatory agencies to evaluate drug nephrotoxicity across various settings. We believe that this is the first step to recognizing drug-induced kidney disease and developing strategies to prevent and manage this condition

Neutrophil Gelatinase-Associated Lipocalin as a Promising Biomarker in Acute Kidney Injury

Acute kidney injury (AKI) is a common complication in several settings inside and outside hospitals. It affects millions of people around the world, and despite high levels of research funding, there is no specific treatment that changes the disease course. The basis for unfavorable outcomes related to this disease is the failure to provide early diagnosis. Currently, the diagnosis of AKI is based on serum creatinine and urine output, and both measures have several limitations, making early diagnosis difficult. In recent decades, several biomarkers of kidney injury have been proposed, with neutrophil gelatinase-associated lipocalin (NGAL) being one of most studied and promising for use in early diagnosis. Despite there being several studies on NGAL, it has not yet been applied in clinical practice; thus, furthering the understanding of the development, interpretation, and limitations of NGAL in the diagnosis of AKI is the objective of this chapter

Angiogenesis in the progression of cutaneous squamous cell carcinoma: an immunohistochemical study of endothelial markers

OBJECTIVE: To demonstrate the role of angiogenesis in the progression of cutaneous squamous cell carcinoma. INTRODUCTION: Angiogenesis is a pivotal phenomenon in carcinogenesis. Its time course in cutaneous squamous cell carcinoma has not yet been fully established. METHODS: We studied the vascular bed in 29 solar keratoses, 30 superficially invasive squamous cell carcinomas and 30 invasive squamous cell carcinomas. The Chalkley method was used to quantify the microvascular area by comparing panendothelial (CD34) with neoangiogenesis (CD105) immunohistochemical markers. The vascular bed from non-neoplastic adjacent skin was evaluated in 8 solar keratoses, 10 superficially invasive squamous cell carcinomas and 10 invasive squamous cell carcinomas. RESULTS: The microvascular area in CD105-stained specimens significantly increased in parallel with cutaneous squamous cell carcinoma progression. However, no differences between groups were found in CD34 sections. Solar keratosis, superficially invasive squamous cell carcinoma and invasive squamous cell carcinoma samples showed significant increases in microvascular area for both CD34- and CD105-stained specimens compared with the respective adjacent skin. DISCUSSION: The angiogenic switch occurs early in the development of cutaneous squamous cell carcinoma, and the rate of neovascularization is parallel to tumor progression. In contrast to panendothelial markers, CD105 use allows a dynamic evaluation of tumor angiogenesis. CONCLUSION: This study demonstrated the dependence of skin carcinogenesis on angiogenesis

Fluid accumulation, recognition and staging of acute kidney injury in critically-ill patients

Abstract Introduction Serum creatinine concentration (sCr) is the marker used for diagnosing and staging acute kidney injury (AKI) in the RIFLE and AKIN classification systems, but is influenced by several factors including its volume of distribution. We evaluated the effect of fluid accumulation on sCr to estimate severity of AKI. Methods In 253 patients recruited from a prospective observational study of critically-ill patients with AKI, we calculated cumulative fluid balance and computed a fluid-adjusted sCr concentration reflecting the effect of volume of distribution during the development phase of AKI. The time to reach a relative 50% increase from the reference sCr using the crude and adjusted sCr was compared. We defined late recognition to estimate severity of AKI when this time interval to reach 50% relative increase between the crude and adjusted sCr exceeded 24 hours. Results The median cumulative fluid balance increased from 2.7 liters on day 2 to 6.5 liters on day 7. The difference between adjusted and crude sCr was significantly higher at each time point and progressively increased from a median difference of 0.09 mg/dL to 0.65 mg/dL after six days. Sixty-four (25%) patients met criteria for a late recognition to estimate severity progression of AKI. This group of patients had a lower urine output and a higher daily and cumulative fluid balance during the development phase of AKI. They were more likely to need dialysis but showed no difference in mortality compared to patients who did not meet the criteria for late recognition of severity progression. Conclusions In critically-ill patients, the dilution of sCr by fluid accumulation may lead to underestimation of the severity of AKI and increases the time required to identify a 50% relative increase in sCr. A simple formula to correct sCr for fluid balance can improve staging of AKI and provide a better parameter for earlier recognition of severity progression

Rationale and Design of the Genetic Contribution to Drug Induced Renal Injury (DIRECT) Study

IntroductionNephrotoxicity from drugs accounts for 18% to 27% of cases of acute kidney injury. Determining a genetic predisposition may potentially be important in minimizing risk. The aims of this study are as follows: to determine whether a genetic predisposition exists for the development of drug-induced kidney disease (DIKD), using genome-wide association and whole-genome sequencing studies; to describe the frequency, course, risk factors, resolution and outcomes of DIKD cases; to investigate the role of ethnic/racial variability in the genetics of DIKD; and to explore the use of different tools establishing causality of DIKD.MethodsA total of 800 patients will be enrolled worldwide and blood samples for DNA collected. Data on the patient risk factors, vital signs, laboratory parameters, drug exposure, and DIKD course will be recorded. A panel of nephrologists will adjudicate all cases. Genome-wide association studies will be conducted using population controls matched on biogeographic ancestry to determine whether there is a genetic predisposition to DIKD. The primary endpoint is the identification of specific drug-related polymorphisms associated with DIKD. Secondary endpoints include the following: frequency of DIKD by causal drug and drug combinations; DIKD genetic variability; exploration of causality assessment tools; risk factor identification; description of the course of DIKD, including mortality and dialysis dependency at hospital discharge and 28 and 90 days post-event.ResultsData are currently being analyzed. Results are pending.DiscussionThe Genetic Contribution to Drug Induced Renal Injury (DIRECT) study will be the first observational cohort study to investigate the genetic determinants of DIKD. If the trial is positive, its findings will potentially translate into safer patient outcomes, by genotypic individualization of therapy and minimization of harm

Circulating Uromodulin inhibits systemic oxidative stress by inactivating the TRPM2 channel

High serum concentrations of kidney-derived protein uromodulin (Tamm-Horsfall protein or THP) have recently been shown to be independently associated with low mortality in both older adults and cardiac patients, but the underlying mechanism remains unclear. Here, we show that THP inhibits the generation of reactive oxygen species (ROS) both in the kidney and systemically. Consistent with this experimental data, the concentration of circulating THP in patients with surgery-induced acute kidney injury (AKI) correlated with systemic oxidative damage. THP in the serum dropped after AKI, and was associated with an increase in systemic ROS. The increase in oxidant injury correlated with post-surgical mortality and need for dialysis. Mechanistically, THP inhibited the activation of the transient receptor potential cation channel, subfamily M, member 2 (TRPM2) channel. Furthermore, inhibition of TRPM2 in vivo in a mouse model, mitigated the systemic increase in ROS during AKI and THP deficiency. Our results suggest that THP is a key regulator of systemic oxidative stress by suppressing TRPM2 activity and our findings might help to explain how circulating THP deficiency is linked with poor outcomes and increased mortality

Distribuição dos diagnósticos histológicos das afecções da pele negra e branca, em Campinas, Brasil, entre 1993 e 2009

INTRODUCTION: Little is known about ethnic differences in the frequency of skin diseases, and even less in terms of Brazilian population, which is characterized by miscegenation. OBJECTIVE: To evaluate the distribution of skin disorders in black and Caucasian patients through pathological specimens. METHODS: 826 biopsies from black-skinned individuals and 1,652 from white-skinned patients were retrieved and studied from the files of the Pathology Department, UNICAMP Hospital within the period of 1993-2009. The clinical data were obtained from medical records and the results were tested by statistical methods. RESULTS: Non-melanoma cancer was the most frequent diagnosis in Caucasians (45%), differing from the frequency among black patients (8%), both arising in sun-exposed skin. Regarding topography and age, in white-skinned patients aged over 50 years, biopsies of head and neck prevailed. As to black patients, the disease predominated among female individuals aged from 15 to 50 years and in the genital area. In the comparative analysis of vulvar diseases, we observed differences in diagnoses of sexually transmitted diseases more common among black women. Excluding cancers and genital lesions, black patients had a higher percentage of infectious diseases. Among the non-infectious diseases, cutaneous lupus was the most frequent diagnosis in both groups. Lichen planus and drug reactions were more frequent in black patients. CONCLUSION: Apart from intrinsic differences among skin types, social factors may interfere in the distribution of diseases. Not only may these results be useful to public health programs, but they may also aid the approach to dermatological diseases in black skin patients.INTRODUÇÃO: Pouco se conhece sobre as diferenças étnicas na frequência das doenças da pele e, menos ainda, na população brasileira, caracterizada pela miscigenação. OBJETIVO: Avaliar a distribuição das afecções da pele de indivíduos negros, comparativamente com a dos brancos, em material anatomopatológico. MÉTODOS: Foram estudadas 826 biópsias de indivíduos de pele negra e 1.652 dos de pele branca, obtidas do Departamento de Anatomia Patológica do Hospital das Clínicas da Universidade Estadual de Campinas (HC-UNICAMP), entre 1993 e 2009. Os achados clínicos foram obtidos dos prontuários e os resultados testados por métodos estatísticos. RESULTADOS: O câncer não melanoma foi o diagnóstico mais frequente nos brancos (45%), diferindo, significantemente, da frequência nos negros (8%), assestando-se, em ambos, na pele exposta ao sol. Quanto à topografia e à idade, nos brancos predominavam biópsias da cabeça e pescoço, na faixa acima dos 50 anos. Nos negros, as doenças predominavam entre 15 e 50 anos, no sexo feminino, na topografia dos genitais. À análise comparativa das doenças vulvares, observou-se diferença nos diagnósticos de doenças sexualmente transmissíveis mais frequentes nas mulheres negras. Excluindo-se os cânceres e a topografia genital, os negros apresentaram porcentagem maior de doenças infecciosas. Entre as doenças não infecciosas, o lúpus cutâneo foi a mais frequente nos dois grupos; o líquen plano e a farmacodermia foram mais frequentes nos negros. CONCLUSÃO: Além das diferenças intrínsecas de tipos de pele, fatores sociais podem atuar na distribuição das doenças. Esses resultados podem ser úteis, tanto para os programas de saúde pública quanto para a abordagem das doenças dermatológicas nos pacientes de pele negra.267272Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Long-Term Follow-Up of Patients after Acute Kidney Injury: Patterns of Renal Functional Recovery

Background and Objectives: Patients who survive acute kidney injury (AKI), especially those with partial renal recovery, present a higher long-term mortality risk. However, there is no consensus on the best time to assess renal function after an episode of acute kidney injury or agreement on the definition of renal recovery. In addition, only limited data regarding predictors of recovery are available. Design, Setting, Participants, & Measurements: From 1984 to 2009, 84 adult survivors of acute kidney injury were followed by the same nephrologist (RCRMA) for a median time of 4.1 years. Patients were seen at least once each year after discharge until end stage renal disease (ESRD) or death. In each consultation serum creatinine was measured and glomerular filtration rate estimated. Renal recovery was defined as a glomerular filtration rate value $60 mL/min/1.73 m2. A multiple logistic regression was performed to evaluate factors independently associated with renal recovery. Results: The median length of follow-up was 50 months (30–90 months). All patients had stabilized their glomerular filtration rates by 18 months and 83 % of them stabilized earlier: up to 12 months. Renal recovery occurred in 16 patients (19%) at discharge and in 54 (64%) by 18 months. Six patients died and four patients progressed to ESRD during the follow up period. Age (OR 1.09, p,0.0001) and serum creatinine at hospital discharge (OR 2.48, p = 0.007) were independent factors associated with non renal recovery. The acute kidney injury severity, evaluated by peak serum creatinine and nee

Three little pieces for computer and relativity

Numerical relativity has made big strides over the last decade. A number of problems that have plagued the field for years have now been mostly solved. This progress has transformed numerical relativity into a powerful tool to explore fundamental problems in physics and astrophysics, and I present here three representative examples. These "three little pieces" reflect a personal choice and describe work that I am particularly familiar with. However, many more examples could be made.Comment: 42 pages, 11 figures. Plenary talk at "Relativity and Gravitation: 100 Years after Einstein in Prague", June 25 - 29, 2012, Prague, Czech Republic. To appear in the Proceedings (Edition Open Access). Collects results appeared in journal articles [72,73, 122-124