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The article discusses the importance of kidney functional reserve (KFR) in the early detection of subclinical chronic kidney disease (CKD). CKD affects a significant portion of the global population, particularly in low- to middle-income countries, and is a major risk factor for end-stage renal disease and cardiovascular disease. Current biomarkers for CKD, such as serum creatinine and estimated glomerular filtration rate, are inefficient in detecting early-stage CKD. The study by Taylor et al. demonstrates that a reduction in KFR can detect subclinical CKD that is otherwise undetectable using traditional biomarkers. This finding has significant diagnostic and translational value and can guide early intervention to prevent the progression of CKD. [Extracted from the article]

Since the start of the COVID-19 pandemic, several manifestations of kidney involvement associated with infection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus have been described, including proteinuria, hematuria, and acute kidney injury. A growing body of literature has explored the risk factors and pathogenesis of COVID-19-associated acute kidney injury (AKI), including direct and indirect mechanisms, as well as early postdischarge outcomes that may result from various manifestations of kidney involvement. In this review, we explore the current state of knowledge of the epidemiology of COVID-19- associated AKI, potential mechanisms and pathogenesis of AKI, and various management strategies for patients in the acute setting. We highlight how kidney replacement therapy for patients with COVID-19-associated AKI has been affected by the increasing demand for dialysis and how the postacute management of patients, including outpatient follow-up, is vitally important. We also review what is presently known about long-term kidney outcomes after the initial recovery from COVID-19. We provide some guidance as to the management of patients hospitalized with COVID-19 who are at risk for AKI as well as for future clinical research in the setting of COVID-19 and the significance of early identification of patients at highest risk for adverse kidney outcomes. [ABSTRACT FROM AUTHOR]

Despite advancements in standardizing the criteria for acute kidney injury (AKI), its definition remains based on changes in serum creatinine and urinary output that do not specifically represent tubular function or injury and that have significant limitations in the acute hospital setting. Much effort in nephrology has centered on identifying biomarkers of AKI to address these limitations. This review summarizes recent advances in our knowledge of biomarkers involved in pathophysiological processes during AKI and describes their potential clinical implications. Blood and urine biomarkers are released via various mechanisms during renal tubular injury. Urinary kidney injury molecule-1 (KIM-1), liver-type fatty acid binding protein (L-FABP), insulin-like growth factor-binding protein-7 (IGFBP-7), and tissue inhibitor of metalloprotease-2 (TIMP-2) are released from the proximal tubule while uromodulin (UMOD) is secreted from the loop of Henle and neutrophil gelatinase-associated lipocalin (NGAL) is released from the distal tubule. These biomarkers could therefore be used to localize specific segments of injured tubules. Biomarkers also have diverse roles in pathophysiological processes in AKI, including inflammation, repair, and fibrosis. Current evidence suggests that these biomarkers could be used to predict the transition to chronic kidney disease (CKD), decrease discard of AKI kidneys, differentiate between kidney dysfunction and injury, guide AKI management, and improve diagnosis of diseases such as acute interstitial nephritis (AIN). They could differentiate between disease phenotypes, facilitate the inclusion of a homogenous patient population in future trials of AKI, and shed light on therapeutic pathways to prevent the transition from AKI to CKD. However, a major limitation of current biomarker research in AKI is the lack of tissue correlation. The Kidney Precision Medicine Project, a large-scale national effort, is currently underway to construct a kidney tissue atlas and expand the use of biomarkers to assess nephron health. Numerous biomarkers are involved in distinct pathophysiological processes after kidney injury and have demonstrated potential to improve diagnosis and risk stratification as well as provide a prognosis for patients with AKI. Some biomarkers are ready for use in clinical trials of AKI and could guide management in various clinical settings. Further investigation of these biomarkers will provide insight that can be applied to develop novel therapeutic agents for AKI. [ABSTRACT FROM AUTHOR]

Motivated by a study of acute kidney injury, we consider the setting of biomarker studies involving patients at multiple centers where the goal is to develop a biomarker combination for diagnosis, prognosis, or screening. As biomarker studies become larger, this type of data structure will be encountered more frequently. In the presence of multiple centers, one way to assess the predictive capacity of a given combination is to consider the center‐adjusted area under the receiver operating characteristic curve (aAUC), a summary of the ability of the combination to discriminate between cases and controls in each center. Rather than using a general method, such as logistic regression, to construct the biomarker combination, we propose directly maximizing the aAUC. Furthermore, it may be desirable to have a biomarker combination with similar performance across centers. To that end, we allow for penalization of the variability in the center‐specific AUCs. We demonstrate desirable asymptotic properties of the resulting combinations. Simulations provide small‐sample evidence that maximizing the aAUC can lead to combinations with improved performance. We also use simulated data to illustrate the utility of constructing combinations by maximizing the aAUC while penalizing variability. Finally, we apply these methods to data from the study of acute kidney injury. [ABSTRACT FROM AUTHOR]

The last two decades have witnessed an explosion in research focused on the development and assessment of novel biomarkers for improved prognosis of diseases. As a result, best practice standards guiding biomarker research have undergone extensive development. Currently, there is great interest in the promise of biomarkers to enhance research efforts and clinical practice in the setting of chronic kidney disease, acute kidney injury, and glomerular disease. However, some have questioned whether biomarkers currently add value to the clinical practice of nephrology. The current state of the art pertaining to statistical analyses regarding the use of such measures is critical. In December 2014, the National Institute of Diabetes and Digestive and Kidney Diseases convened a meeting, "Toward Building Better Biomarker Statistical Methodology," with the goals of summarizing the current best practice recommendations and articulating new directions for methodological research. This report summarizes its conclusions and describes areas that need attention. Suggestions are made regarding metrics that should be commonly reported. We outline the methodological issues related to traditional metrics and considerations in prognostic modeling, including discrimination and case mix, calibration, validation, and cost-benefit analysis. We highlight the approach to improved risk communication and the value of graphical displays. Finally, we address some "new frontiers" in prognostic biomarker research, including the competing risk framework, the use of longitudinal biomarkers, and analyses in distributed research networks. [ABSTRACT FROM AUTHOR]

Many investigators are interested in combining biomarkers to predict a binary outcome or detect underlying disease. This endeavor is complicated by the fact that many biomarker studies involve data from multiple centers. Depending upon the relationship between center, the biomarkers, and the target of prediction, care must be taken when constructing and evaluating combinations of biomarkers. We introduce a taxonomy to describe the role of center and consider how a biomarker combination should be constructed and evaluated. We show that ignoring center, which is frequently done by clinical researchers, is often not appropriate. The limited statistical literature proposes using random intercept logistic regression models, an approach that we demonstrate is generally inadequate and may be misleading. We instead propose using fixed intercept logistic regression, which appropriately accounts for center without relying on untenable assumptions. After constructing the biomarker combination, we recommend using performance measures that account for the multicenter nature of the data, namely the center-adjusted area under the receiver operating characteristic curve. We apply these methods to data from a multicenter study of acute kidney injury after cardiac surgery. Appropriately accounting for center, both in construction and evaluation, may increase the likelihood of identifying clinically useful biomarker combinations. [ABSTRACT FROM AUTHOR]

The current unidimensional paradigm of kidney disease detection is incompatible with the complexity and heterogeneity of renal pathology. The diagnosis of kidney disease has largely focused on glomerular filtration, while assessment of kidney tubular health has notably been absent. Following insult, the kidney tubular cells undergo a cascade of cellular responses that result in the production and accumulation of low-molecular-weight proteins in the urine and systemic circulation. Modern advancements in molecular analysis and proteomics have allowed the identification and quantification of these proteins as biomarkers for assessing and characterizing kidney diseases. In this review, we highlight promising biomarkers of kidney tubular health that have strong underpinnings in the pathophysiology of kidney disease. These biomarkers have been applied to various specific clinical settings from the spectrum of acute to chronic kidney diseases, demonstrating the potential to improve patient care. [ABSTRACT FROM AUTHOR]

Kidney involvement is common in patients with acute SARS-CoV-2 infection, and subclinical inflammation and injury may persist for many months, resulting in a progressive decline in kidney function that leads to chronic kidney disease. Continued research is imperative to understand these long-term sequelae and identify interventions to mitigate them. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a common hospital complication. There are no effective treatments to minimize kidney injury or limit associated morbidity and mortality. Currently, serum creatinine and urine output remain the gold standard used clinically in the diagnosis of AKI. Several novel biomarkers can diagnose AKI earlier than elevations of serum creatinine and changes in urine output. Recent long-term observational studies have elucidated a subgroup of patients who have positive biomarkers of AKI but do not meet criteria for AKI by serum creatinine or urine output, termed subclinical AKI. These patients with subclinical AKI have increased risk of both short- and long-term mortality. In this review, we will highlight the implications of what these patients may represent and the need for better phenotyping of AKI by etiology, severity of injury, and ability to recover. We will discuss two AKI biomarkers, neutrophil gelatinase-associated lipocalin (NGAL) and breast regression protein-39 (BRP-39)/YKL-40, that exemplify the need to characterize the complexity of the biological meaning behind the biomarker, beyond elevated levels reporting on tissue injury. Ultimately, careful phenotyping of AKI will lead to identification of therapeutic targets and appropriate patient populations for clinical trials. [ABSTRACT FROM AUTHOR]

Background: Higher levels of plasma neutrophil gelatinase-associated lipocalin (pNGAL) are an early marker of acute kidney injury and are associated with increased risk of short-term adverse outcomes. The independent association between pNGAL and long-term mortality is unknown. Methods: In this prospective observational cohort study, we studied 1191 adults who underwent cardiac surgery between 2007 and 2009 at 6 centers in the TRIBE-AKI cohort. We measured the pNGAL on the pre-operative and first 3 post-operative days and assessed the relationship of peri-operative pNGAL concentrations with all-cause mortality. Results: During a median follow-up of 3.0 years, 139 participants died (50/1000 person-years). Pre-operative levels of pNGAL were associated with 3-year mortality (unadjusted HR 1.96, 95% CI 1.34,2.85) and the association persisted after adjustment for pre-operative variables including estimated glomerular filtration rate (adjusted HR 1.48, 95% CI 1.04–2.12). After adjustment for pre- and intra-operative variables, including pre-operative NGAL levels, the highest tertiles of first post-operative and peak post-operative pNGAL were also independently associated with 3-year mortality risk (adjusted HR 1.31, 95% CI 1.0–1.7 and adjusted HR 1.78, 95% CI 1.2–2.7, respectively). However, after adjustment for peri-operative changes in serum creatinine, there was no longer an independent association between the first post-operative and peak post-operative pNGAL and long-term mortality (adjusted HR 0.98,95% CI 0.79–1.2 for first pNGAL and adjusted HR 1.19, 95% CI 0.87–1.61 for peak pNGAL). Conclusions: Pre-operative pNGAL levels were independently associated with 3-year mortality after cardiac surgery. While post-operative pNGAL levels were also associated with 3-year mortality, this relationship was not independent of changes in serum creatinine. These findings suggest that while pre-operative pNGAL adds prognostic value for mortality beyond routinely available serum creatinine, post-operative pNGAL measurements may not be as useful for this purpose. [ABSTRACT FROM AUTHOR]

Approximately, 15% of HIV-infected individuals have comorbid diabetes. Studies suggest that HIV and diabetes have an additive effect on chronic kidney disease (CKD) progression; however, this observation may be confounded by differences in traditional CKD risk factors.We studied a national cohort of HIV-infected and matched HIV-uninfected individuals who received care through the Veterans Healthcare Administration. Subjects were divided into 4 groups based on baseline HIV and diabetes status, and the rate of progression to an estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m2 was compared using Cox-proportional hazards modeling to adjust for CKD risk factors.About 31,072 veterans with baseline eGFR ≥45 mL/min/1.73m2 (10,626 with HIV only, 5088 with diabetes only, and 1796 with both) were followed for a median of 5 years. Mean baseline eGFR was 94 mL/min/1.73m2, and 7% progressed to an eGFR < 45 mL/min/1.73m2. Compared with those without HIV or diabetes, the relative rate of progression was increased in individuals with diabetes only [adjusted hazard ratio (HR) 2.48; 95% confidence interval (CI): 2.19 to 2.80], HIV only [HR: 2.80, 95% CI: 2.50 to 3.15], and both HIV and diabetes [HR: 4.47, 95% CI: 3.87 to 5.17].Compared with patients with only HIV or diabetes, patients with both diagnoses are at significantly increased risk of progressive CKD even after adjusting for traditional CKD risk factors. Future studies should evaluate the relative contribution of complex comorbidities and accompanying polypharmacy to the risk of CKD in HIV-infected individuals and prospectively investigate the use of cART, glycemic control, and adjunctive therapy to delay CKD progression. [ABSTRACT FROM AUTHOR]

Progressive disruption of renal tubular integrity in the setting of increased cellular proliferation and apoptosis is a feature of autosomal dominant polycystic kidney disease (ADPKD). Here we evaluated the effect of these processes on the expression of Lcn2 (NGAL) and interleukin (IL)-18, markers of tubular injury, in rodent models and in the cyst fluid and urine of patients with ADPKD. Two mouse models where Pkd2 was inactivated, which resulted in early- or adult-onset cysts, were used to evaluate NGAL levels. Further, the Han:SPRD rat model of polycystic disease was used to study IL-18 levels. In four annual serial urine samples collected from 107 patients with ADPKD in the Consortium for Radiologic Imaging for the Study of Polycystic Kidney Disease (CRISP) study, NGAL and IL-18 excretion rates were determined in conjunction with measures of total kidney volume and estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease equation. Kidneys from affected mice and rats showed prominent expression of NGAL and IL-18/IL-18R, respectively, in epithelial cells lining kidney cysts. In human ADPKD cyst fluid, both NGAL and IL-18 were elevated. In CRISP patients, the mean percentage increase in total kidney volume was 5.4/year and the mean decline in eGFR 2.4 ml/min/year. The trend of increased mean urine NGAL and IL-18 over 3 years was statistically significant; however, there was no association between tertiles of IL-18 or quartiles of NGAL and change in total kidney volume or eGFR over this period. Thus, urinary NGAL and IL-18 excretion is mildly and stably elevated in ADPKD, but does not correlate with changes in total kidney volume or kidney function. This may be due, in part, to the lack of communication between individual cysts and the urinary collecting system in this disorder. [ABSTRACT FROM AUTHOR]

The diagnosis and prognosis of acute kidney injury (AKI) by current clinical means is inadequate. Biomarkers of kidney injury that are easily measured and unaffected by physiological variables could revolutionize the management of AKI. Our objective was to systematically review the diagnostic and prognostic utility of urine and serum biomarkers of AKI in humans. We searched MEDLINE, PubMed and EMBASE databases (January 2000-August 2009) for biomarker studies that could be classified into the following categories: (a) confirmation of the diagnosis of established AKI, (b) early prediction of AKI, and (c) prognostication of AKI. We identified 54 manuscripts published since 2000 that met our inclusion and exclusion criteria. Urinary interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL) and N-acetyl-β -D-glucosaminidase (NAG) are potentially useful biomarkers for the diagnosis of established AKI. Urinary NGAL, IL-18, and liver-type fatty acid binding protein, and serum NGAL and cystatin C represent the most promising biomarkers for early prediction of AKI. Urinary cystatin C, α1-microglobulin, NAG and retinol-binding protein may be useful to predict severity and outcomes of AKI. In conclusion, we identified several studies of promising biomarkers for the diagnosis, prediction and prognostication of AKI. However, we note several limitations, including small sample sizes, inadequate gold standard, exclusion of patients with chronic kidney disease, incomplete statistical analyses, utilization of research-based assays and a paucity of studies examining prediction for clinical outcomes. Future studies will need to address these limitations in orderfor further progress to be made. [ABSTRACT FROM AUTHOR]

The article discusses about long-term prognosis of acute kidney injury after acute myocardial infraction. According to the article, acute kidney injury is a usual complication, though the severity with the long-term risk of death is not well established. An observational study was conducted on elderly medicare patients. The research concludes that acute kidney injury has an independent and evaluated relation with long-term mortality. The conclusions should infuse additional mechanistic and interventional researches and plans for follow-up of acute kidney injury patients.

The article introduces new and promising novel biomarkers for acute kidney injury (AKI), with potential high sensitivity and specificity. These biomarkers are classified into plasma panel, which consists of gelatinase-associated lipocalin and cystatin C, and urine panel, which includes neutrophil gelatinase-associated lipocalin, interleukin 18 and kidney injury-molecule 1.

Abstract: Acute kidney injury (AKI) occurs frequently after nonmyeloablative hematopoietic cell transplantation (HCT). The severity of AKI after nonmyeloablative HCT has association with short-term mortality. However, the long-term effect of AKI on survival after nonmyeloablative HCT is not known. We performed a retrospective analysis of patients who underwent an HLA matched nonmyeloablative HCT between 1997 and 2006. Patients were followed for a median of 36 (range: 3-99) months. AKI occurring up to day 100 was defined as a >2-fold increase in serum creatinine or requirement of dialysis. Of the 358 patients who were included in the analysis, 200 (56%) had AKI, 158 (44%) had no AKI. Overall, 158 patients (43%) died during follow-up. After controlling for potential confounders, the adjusted hazard ratio for overall mortality associated with AKI was 1.57 (95 % confidence interval [CI] 1.2-2.3; P = .0006). The adjusted hazards ratio of nonrelapse mortality (NRM) associated with AKI was 1.72 (95% CI 0.9-3.1; P = .07). AKI is an independent predictor of overall mortality after nonmyeloablative HCT. This finding reiterates the importance of identifying preventative strategies in nonmyeloablative HCT for attenuating incidence and severity of AKI. [Copyright &y& Elsevier]

The article investigates the physical function and mental health changes from baseline to 6 months after coronary artery bypass grafting (CABG) surgery. The study found that patients with severe chronic kidney disease (CKD) showed no improvement in physical function despite modification of baseline scores while improvements in mental function were noted in all stages of CKD. The findings suggest that additional studies are needed to improve decision making process in patients following CABG.

Heparin-induced thrombocytopenia (HIT) is characterized by thrombocytopenia and paradoxical hypercoagulability. HIT occurs when an antibody (“HIT antibody”) produced against the complex of heparin and platelet factor 4 (PF4) causes systemic platelet consumption and activation. Nephrologists encounter HIT in the care of end-stage renal disease (ESRD) patients because heparin is a routine anticoagulant in hemodialysis. The incidence of HIT in ESRD appears to be lower than in other clinical settings. However, HIT is equally life threatening in ESRD patients and therefore demands the same prompt recognition and aggressive treatment. Diagnosing HIT requires the detection of HIT antibodies. A functional assay (e.g., [14C] serotonin release assay) relies on the patient's HIT antibodies to activate donor platelets at pharmacologic heparin concentrations. The more common antigen assay (e.g., enzyme-linked immunosorbent assay [ELISA]) detects the binding of the patient's HIT antibodies to antigens (e.g., heparin-PF4 complex) in a microtiter well and does not involve platelets. The moment HIT is suspected, heparin should be stopped and an alternative anticoagulant initiated immediately, even before the result of a serologic test becomes available. The advent of several new anticoagulants in the last decade, especially argatroban and bivalirudin, has expanded treatment options for HIT in dialysis patients. This review discusses the epidemiology, pathogenesis, clinical features, diagnosis, and treatment of HIT, with special emphasis on concepts relevant to the care of dialysis patients. [ABSTRACT FROM AUTHOR]

Arterial stiffness is an independent cardiovascular prognostic factor and is modulated by angiotensin-converting enzyme inhibitors (ACEIs). The authors performed a meta-analysis of clinical trials investigating the effects of ACEIs on pulse wave velocity (PWV) or augmentation index. The search included randomized clinical trials as well as uncontrolled studies that measured in-treatment changes in arterial stiffness. The authors performed separate analyses for carotid-femoral PWV, brachioradial PWV, and augmentation index. Average absolute and relative reduction in mean arterial pressure and PWV were -15.4 mm Hg and -13.04% and -1.15 m/s and -9.74% for carotid-femoral PWV studies; and -11.2 mm Hg and -9.3% and -1.9 m/s and -16.7% for brachioradial PWV studies. There was a greater reduction in augmentation index by ACEIs when compared with controls (-1.0% to -5.3%). The authors conclude that ACEIs have modest beneficial effects on arterial stiffness measured as PWV and augmentation index, and this effect is at least partly independent of changes in blood pressure. [ABSTRACT FROM AUTHOR]

Acute renal failure independently predicts mortality after myeloablative allogeneic hematopoietic cell transplant. Background. Patients undergoing myeloablative allogeneic hematopoietic cell transplantation (HCT) have a high incidence of acute renal failure (ARF). However, it is unclear if ARF is independently associated with mortality after this procedure. Methods. We performed meta-analysis of published reports on ARF after myeloablative allogeneic HCT. Four databases (MEDLINE, Cochrane Library, PubMed, Web of Science) and hand searching of conference proceedings were used to identify the studies. ARF was defined as the doubling of serum creatinine occurring within the first 100 days after HCT. The absolute and the relative risks for death after ARF were calculated for every study. The combined relative risk was calculated using the random effects model. Also, multivariate analysis of patient level data was performed on patients from The University of Colorado to establish independent association between ARF and mortality. Results. One thousand two hundred and eleven patients were included in the meta-analysis from the 6 published reports in the literature. The overall incidence of ARF varied from 42% to 84% in these studies. On combining the studies by random-effects model, the relative risk of death after ARF was 2.22 (95%CI 1.38–3.5, P< 0.001). The analysis of patient level data from the University of Colorado demonstrated increasing mortality with worsening grades of ARF. After controlling for various demographic and clinical variables with logistic regression, patients who required dialysis had a 6.8-fold higher association with mortality. Conclusion. ARF appears to independently influence mortality after myeloablative allogeneic HCT. Future studies should be aimed at interventions that can reduce the incidence and severity of ARF with this procedure. [ABSTRACT FROM AUTHOR]

Chuang P, Parikh CR, Langone A. Urinary tract infections after renal transplantation: a retrospective review at two US transplant centers.Clin Transplant 2005 DOI: 10.1111/j.1399-0012.2005.00327.x© Blackwell Munksgaard, 2005Urinary tract infections (UTIs) are the most common infectious complication following renal transplantation. Previous studies uniformly report that renal transplant recipients develop UTIs more often than the general population, but widely differ on how frequently UTIs occur after transplantation. These studies also disagree on the risk factors associated with developing post-transplant UTIs, as well as the effect that UTIs may have on graft outcomes and patient mortality. We performed a retrospective cohort study including all the adult patients who received a renal transplant at two US transplant centers from January 1996 to December 2002 (500 patients). Two hundred and thirteen (43%) patients developed one or more post-transplant UTIs over a mean follow-up period of 42 months. Significant risk factors for post-transplant UTIs were advanced age, female gender, reflux kidney disease, use of azathioprine and cadaveric donor. UTIs did not increase risk for renal graft loss, but were associated with increased mortality (3.5 odds ratio, 95% confidence interval 1.68–7.23). We conclude UTIs may be associated with an increased mortality risk in renal transplant recipients. Prevention of UTIs in high-risk renal transplant patients or those with recurrent UTIs may possibly decrease post-transplant mortality. [ABSTRACT FROM AUTHOR]

Renal dysfunction in allogeneic hematopoietic cell transplantation. Background. Allogeneic hematopoietic cell transplantation (HCT), formerly called bone marrow transplantation, can potentially cure various malignant and non-malignant diseases, but it is associated with a high risk of toxicity. We have previously shown an overall 21% incidence of severe acute renal failure in patients undergoing autologous HCT. The present study evaluated renal dysfunction in patients undergoing allogeneic HCT. Methods. The clinical course of 88 adult patients who received allogeneic HCT at the University of Colorado Health Science Center was analyzed. Renal dysfunction was classified as follows: Grade 0 = normal renal function; Grade 1 =>25% decrement in GFR but twofold increase in serum creatinine; Grade 3 =>twofold increase in serum creatinine and need for dialysis. Results. Of the 88 patients, 81 (92%) patients had some degree of renal dysfunction (Grade 1, 20 patients; Grade 2, 32 patients; Grade 3, 29 patients). Severe nephrotoxicity (Grade 2 and Grade 3 renal dysfunction) was associated with significantly higher frequencies of sepsis, hepatic toxicity and hepatic veno-occlusive disease (VOD), and lung toxicity. The overall mortality rate at the end of 6 months was 58%. Grade 3 renal dysfunction was associated with a significantly increased risk of mortality (82.6%). Conclusion. A 92% incidence of renal dysfunction in allogeneic HCT patients was found. Lung and liver toxicities were significantly correlated with developing renal dysfunction, and the mortality rates for patients with Grade 3 renal failure exceeded 80%. [ABSTRACT FROM AUTHOR]

\nIntroduction: Cardiac function is important to quantify for risk stratification. Although left ventricular ejection fraction (LVEF) is commonly used, and identifies patients with poor systolic function, other easily acquired measures of cardiac function are needed, particularly to stratify patients with relatively preserved LVEF. LV relative wall thickness (RWT) has been associated with adverse clinical outcomes in patients with preserved LVEF, but the clinical relevance of this observation is not known. The purpose of this study was to assess whether increased RWT is a marker of subclinical cardiac dysfunction as measured by a surrogate of LV dysfunction and left ventricular ejection time (LVET) and if increased RWT is independently associated with chronic kidney disease (CKD), an important clinical outcome and cardiovascular disease risk equivalent. Methods: This retrospective cohort study enrolled ambulatory patients 18 years and older undergoing routine transthoracic echocardiography (TTE) at Johns Hopkins Hospital from January 2017 to January 2018. Patients with LVEF <50%, severe valvular disease, or liver failure were excluded. Multivariable regression evaluated the relationship between RWT, LVET, and CKD adjusted for demographics, comorbidities, and vital signs. Results: We analyzed data from 375 patients with mean age (±SD) 52.2 ± 15.3 years of whom 58% were female. Mean ± SD of RWT was 0.45 ± 0.10, while mean ± SD of LVET was 270 ms ± 33. In multivariable linear regression adjusted for demographics, comorbidities, vital signs, and left ventricular mass, each 0.1 increase in RWT was associated with a decrease of 4.6 ms in LVET, indicating worse cardiac function (β, ± 95% CI) (−4.60, −7.37 to −1.48, p = 0.004). Of those with serum creatinine available 1 month before or after TTE, 20% (50/247) had stage 3 or greater CKD. In logistic regression (adjusted for sex, comorbidities, and medications), each 0.1 unit increase in RWT was associated with an 61% increased odds of CKD (aOR = 1.61, 1.03–2.53, p = 0.037). In multivariable ordinal regression adjusted for the same covariates, each 0.1 unit increase in RWT was associated with a 44% increased odds of higher CKD stage (aOR = 1.44, 1.03–2.02, p = 0.035). There was a trend but no statistically significant relationship between RWT and change in estimated glomerular filtration rate at 1 year. Conclusion: In an outpatient cohort undergoing TTE, increased RWT was independently associated with a surrogate of subclinical systolic dysfunction (LVET) and CKD. This suggests that RWT, an easily derived measure of LV geometry on TTE, may identify clinically relevant subclinical systolic dysfunction and patients with worse kidney function. Additional investigation to further clarify the relationships between RWT, systolic function, and kidney dysfunction over time and how this information may guide clinical intervention are warranted. Cardiac function is important to quantify for risk stratification. Although left ventricular ejection fraction is commonly used, and identifies patients with poor systolic function, other easily acquired measures of cardiac function are needed. In this retrospective cohort study of 375 patients with increased left ventricular relative wall thickness, an easily derived measure from standard transthoracic echocardiography was independently associated with a surrogate of subclinical systolic dysfunction, left ventricular ejection time, and chronic kidney disease. Left ventricular geometry identifies clinically relevant subclinical systolic dysfunction and patients with worse kidney function. [ABSTRACT FROM AUTHOR]

This Commentary discusses concepts related to the development of the point-of-care (POC) diagnostic system and its advantages and disadvantages. Also discussed are the patient, provider, and financial outcomes that ought to be evaluated before the POC test becomes available for clinical use. [ABSTRACT FROM AUTHOR]

This Commentary discusses concepts related to the development of the point-of-care (POC) diagnostic system and its advantages and disadvantages. Also discussed are the patient, provider, and financial outcomes that ought to be evaluated before the POC test becomes available for clinical use.Kidney International (2009) 76, 8–10. doi:10.1038/ki.2009.125 [ABSTRACT FROM AUTHOR]

Key Points: Question: Are kidneys from deceased donors who underwent dialysis prior to kidney donation associated with adverse graft outcomes in kidney transplant recipients compared with kidneys from deceased donors who did not undergo dialysis? Findings: In an analysis of 1944 kidney transplant recipients (including 954 who received kidneys from deceased donors who underwent dialysis prior to kidney donation), the incidence of delayed graft function was higher in recipients of kidneys from deceased donors who underwent dialysis prior to kidney donation vs recipients of kidneys from deceased donors who did not undergo dialysis (59.2% vs 24.6%, respectively), but there were no significant differences in the incidence of graft failure (adjusted odds ratio, 0.90) or mortality (adjusted hazard ratio, 0.76) at a median follow-up of 34.1 months. Meaning: Compared with recipients of kidneys from deceased donors who did not undergo dialysis, receiving kidneys from deceased donors who underwent dialysis prior to donation was associated with a higher incidence of delayed graft function, but no difference in graft failure or death at longer-term follow-up. Importance: Recipient outcomes after kidney transplant from deceased donors who received dialysis prior to kidney donation are not well described. Objective: To compare outcomes of transplant recipients who received kidneys from deceased donors who underwent dialysis prior to kidney donation vs recipients of kidneys from deceased donors who did not undergo dialysis. Design, Setting, and Participants: A retrospective cohort study was conducted including data from 58 US organ procurement organizations on deceased kidney donors and kidney transplant recipients. From 2010 to 2018, 805 donors who underwent dialysis prior to kidney donation were identified. The donors who underwent dialysis prior to kidney donation were matched 1:1 with donors who did not undergo dialysis using a rank-based distance matrix algorithm; 1944 kidney transplant recipients were evaluated. Exposure: Kidney transplants from deceased donors who underwent dialysis prior to kidney donation compared with kidney transplants from deceased donors who did not undergo dialysis. Main Outcomes and Measures: The 4 study outcomes were delayed graft function (defined as receipt of dialysis by the kidney recipient ≤1 week after transplant), all-cause graft failure, death-censored graft failure, and death. Results: From 2010 to 2018, 1.4% of deceased kidney donors (805 of 58 155) underwent dialysis prior to kidney donation. Of these 805 individuals, 523 (65%) donated at least 1 kidney. A total of 969 kidneys (60%) were transplanted and 641 kidneys (40%) were discarded. Among the donors with kidneys transplanted, 514 (mean age, 33 years [SD, 10.8 years]; 98 had hypertension [19.1%] and 36 had diabetes [7%]) underwent dialysis prior to donation and were matched with 514 (mean age, 33 years [SD, 10.9 years]; 98 had hypertension [19.1%] and 36 had diabetes [7%]) who did not undergo dialysis. Kidney transplants from donors who received dialysis prior to donation (n = 954 kidney recipients) were associated with a higher risk of delayed graft function compared with kidney transplants from donors who did not receive dialysis (n = 990 kidney recipients) (59.2% vs 24.6%, respectively; adjusted odds ratio, 4.17 [95% CI, 3.28-5.29]). The incidence rates did not significantly differ at a median follow-up of 34.1 months for all-cause graft failure (43.1 kidney transplants per 1000 person-years from donors who received dialysis prior to donation vs 46.9 kidney transplants per 1000 person-years from donors who did not receive dialysis; adjusted hazard ratio [HR], 0.90 [95% CI, 0.70-1.15]), for death-censored graft failure (22.5 vs 20.6 per 1000 person-years, respectively; adjusted HR, 1.18 [95% CI, 0.83-1.69]), or for death (24.6 vs 30.8 per 1000 person-years; adjusted HR, 0.76 [95% CI, 0.55-1.04]). Conclusions and Relevance: Compared with receiving a kidney from a deceased donor who did not undergo dialysis, receiving a kidney from a deceased donor who underwent dialysis prior to kidney donation was associated with a significantly higher incidence of delayed graft function, but no significant difference in graft failure or death at follow-up. This study compares the outcomes of kidney transplant recipients who received kidneys from deceased donors who underwent dialysis prior to kidney donation vs recipients of kidneys from deceased donors who did not undergo dialysis. [ABSTRACT FROM AUTHOR]

Steatotic liver disease (SLD) is a worldwide public health problem, causing considerable morbidity and mortality. Patients with SLD are at increased risk for major adverse cardiovascular (CV) events, type 2 diabetes mellitus and chronic kidney disease. Conversely, patients with cardiometabolic conditions have a high prevalence of SLD. In addition to epidemiological evidence linking many of these conditions, there is evidence of shared pathophysiological processes. In December 2022, a unique multi‐stakeholder, multi‐specialty meeting, called MOSAIC (Metabolic multi Organ Science Accelerating Innovation in Clinical Trials) was convened to foster collaboration across metabolic, hepatology, nephrology and CV disorders. One of the goals of the meeting was to consider approaches to drug development that would speed regulatory approval of treatments for multiple disorders by combining liver and cardiorenal endpoints within a single study. Non‐invasive tests, including biomarkers and imaging, are needed in hepatic and cardiorenal trials. They can be used as trial endpoints, to enrich trial populations, to diagnose and risk stratify patients and to assess treatment efficacy and safety. Although they are used in proof of concept and phase 2 trials, they are often not acceptable for regulatory approval of therapies. The challenge is defining the optimal combination of biomarkers, imaging and morbidity/mortality outcomes and ensuring that they are included in future trials while minimizing the burden on patients, trialists and trial sponsors. This paper provides an overview of some of the wide array of CV, liver and kidney measurements that were discussed at the MOSAIC meeting. [ABSTRACT FROM AUTHOR]

Serum creatinine levels are insensitive to real-time changes in kidney function or injury. There is a growing interest in assessing kidney injury by measuring biomarkers in body fluid. From our previous studies, we identified and reported three urinary biomarkers namely Uromodulin (UMOD), Osteopontin (OPN), and Interleukin-9 (IL-9) to be associated with kidney health. The availability of a rapid point-of-care test for these urinary biomarkers will potentially accelerate its applicability and accessibility. In this study, we aimed to develop novel lateral flow device (LFD) for UMOD, OPN and IL-9. We tested paired antibodies using Enzyme Linked Immunosorbent Assay wherein we observed functionality only for UMOD and OPN and not for IL-9. A conjugation buffer pH of 7.8 and 8.5 was found suitable at a detection antibody concentration of 15 µg/mL for LFD development. The developed LFDs were found to quantitatively measure UMOD standard (LLOD of 80,000 pg/mL) and OPN standard (LLOD of 8600 pg/mL) respectively. The LFD was also able to measure human urinary UMOD and OPN with a percent CV of 12.12 and 5.23 respectively. [ABSTRACT FROM AUTHOR]

Background: Children undergoing cardiac surgery are at risk of high blood pressure (BP), a risk factor for cardiovascular and kidney disease. Twenty-four-hour ambulatory BP monitoring (ABPM) is a reference standard hypertension (HTN) test. Little data exist on ABPM abnormalities in children several years post cardiac surgery. This study aimed to (a) determine ABPM feasibility; (b) describe and compare ABPM measures and abnormalities (percent load, masked HTN [MH]; non-dipping, mean systolic/diastolic BP > 95th percentile; pre-HTN (ABPM); white-coat HTN [WCH]) to casual BP; and (c) compare BP in patients with and without acute kidney injury (AKI). Methods: Prospective, follow-up pilot study of children (0–18 years) who underwent cardiac surgery from 2007 to 2009 at Montreal Children's Hospital. We recorded if participants had post-operative AKI and assessed the following outcomes at 9-year follow-up: casual BP classified by three single-visit measures (normal; elevated BP [eBPSingleVisit]; HTNSingleVisit); ABPM. Bivariable analyses were used to compare characteristics between groups. Results: Twenty-three patients (median [interquartile range], 8.6 [8.0, 9.0] years post cardiac surgery) were included; 16 (70%) male. Six participants (26%) had eBPSingleVisit or higher. On ABPM, 11 (48%) had ≥ 1 abnormality: 9 (39%) had non-dipping; 3 (13%) had pre-HTN; 3 (13%) had WCH; none had HTN or MH. There were no differences in ABPM according to AKI status. Conclusion: Our pilot study determined that ABPM was feasible in children years after cardiac surgery and frequently identified ABPM abnormalities. Future research in larger populations is needed to define specific risk factors for HTN in children after cardiac surgery. [ABSTRACT FROM AUTHOR]

The article presents the discussion on exciting developments in kidney research having the potential in transforming treatment beyond dialysis and transplantation. Topics include wearable artificial kidney and implantable bioartificial kidney having the potential in providing continuous dialysis throughout the day; and clinical trial being stopped early due to technical issues showing variable flow rates and carbon dioxide bubbles in the dialysis circuit.

Cardiac surgery often requires the use of cardiopulmonary bypass, which can cause an inflammatory cascade that results in acute kidney injury (AKI). A recent post hoc analysis of a placebo-controlled, randomized trial suggests that intraoperative steroids might lower the risk of renal replacement therapy for AKI after cardiac surgery. [ABSTRACT FROM AUTHOR]

Experimental models suggest an important role for mitochondrial dysfunction in the pathogenesis of chronic kidney disease (CKD) and acute kidney injury (AKI), but little is known regarding the impact of common mitochondrial genetic variation on kidney health. We sought to evaluate associations of inherited mitochondrial DNA (mtDNA) variation with risk of CKD and AKI in a large population-based cohort. We categorized UK Biobank participants who self-identified as white into eight distinct mtDNA haplotypes, which were previously identified based on their associations with phenotypes associated with mitochondrial DNA copy number, a measure of mitochondrial function. We used linear and logistic regression models to evaluate associations of these mtDNA haplotypes with estimated glomerular filtration rate by serum creatinine and cystatin C (eGFRCr-CysC, N = 362,802), prevalent (N = 416 cases) and incident (N = 405 cases) end-stage kidney disease (ESKD), AKI defined by diagnostic codes (N = 14,170 cases), and urine albumin/creatinine ratio (ACR, N = 114,662). The mean age was 57 ± 8 years and the mean eGFR was 90 ± 14 ml/min/1.73 m2. MtDNA haplotype was significantly associated with eGFR (p = 2.8E−12), but not with prevalent ESKD (p = 5.9E−2), incident ESKD (p = 0.93), AKI (p = 0.26), or urine ACR (p = 0.54). The association of mtDNA haplotype with eGFR remained significant after adjustment for diabetes mellitus and hypertension (p = 1.2E−10). When compared to the reference haplotype, mtDNA haplotypes I (β = 0.402, standard error (SE) = 0.111; p = 2.7E−4), IV (β = 0.430, SE = 0.073; p = 4.2E−9), and V (β = 0.233, SE = 0.050; p = 2.7E−6) were each associated with higher eGFR. Among self-identified white UK Biobank participants, mtDNA haplotype was associated with eGFR, but not with ESKD, AKI or albuminuria. [ABSTRACT FROM AUTHOR]

Experiments in mouse models have shown that the complement cascade is activated within the kidney after ischemia-reperfusion and that complement activation contributes to tubular injury in this setting. Less is known, however, about complement activation in human kidneys after ischemia or whether complement activation in the tubulointerstitium can be detected by measurement of complement fragments in the urine. We hypothesized that urine biomarkers of complement activation would rapidly increase in patients who develop ischemic acute kidney injury, signaling complement activation within the kidney. We confirmed that the alternative pathway of complement is activated in the kidneys of mice after ischemia-reperfusion, and we found that levels of factor B fragments (generated during alternative pathway activation) rapidly increase in the urine. We next performed a case-control study in which we measured complement fragments in human urine samples from patients undergoing cardiac surgery using ELISAs. The level of Ba increased after cardiac surgery and was significantly higher in patients who developed acute kidney injury. The increase in Ba also correlated with magnitude of the subsequent rise in serum creatinine and with the need for hemodialysis during the hospitalization. These findings demonstrate that the alternative pathway of complement is activated in patients who develop acute kidney injury after cardiac surgery and that increases in the level of urine Ba may be a predictive and functional biomarker of severe kidney injury. [ABSTRACT FROM AUTHOR]

A response by M. Zappitelli and colleagues to a letter to the editor on their article "Early postoperative serum cystatin C predicts severe acute kidney injury following pediatric cardiac surgery" in the 2011 issue is presented.

The article discusses the clinical practice and research involved prerenal azotemia. According to the author, the idea of prerenal azotemia is integrated in the clinical practice of nephrology. Some researchers claim that the separation of prerenal azotemia from acute tubular necrosis (ATN) is flawed, unnecessary and unfeasible. The author claims that AKI that involves true structural kidney injury could still be of short term.

A letter to the editor is presented in response to the article "Biomarkers For The Diagnosis and Risk Stratification of Acute Kidney Injury: A Systematic Review" by S. G. Coca, R. Yalavarthy and J. Concato in a previous issue.

The article presents a case study of a 59-year-old Caucasian woman who was evaluated of renal magnesium wasting. She had developed hypomagnesaemia after she underwent multiple ileal resections. She had a dependable ileostomy output of about two liters a day. The article discusses hypomagnesaemia, a disease associated with chest discomfort and weakness which can be cured through magnesium medication.

A letter to the editor is presented in response to an article presented by Dr. Mangano and colleagues regarding long-term mortality associated with aprotinin following coronary artery bypass craft surgery.

A letter to the editor is presented in response to the article "Diurnal blood pressure pattern and risk of congestive heart failure," by E. Ingelsson, K. Bjorkund-Bodegard, and L. Lind in a previous issue.

Chronic kidney disease (CKD) has become a significant public health concern, as it is associated with substantial morbidity. Prior research has evaluated multiple novel CKD biomarkers to supplement serum creatinine and proteinuria. The ultimate goal of this research is to find biomarkers that can be used to accurately predict CKD progression and to better time outpatient follow-up, and referral for transplant. Also, an optimal panel of biomarkers can augment the predictive value of proteinuria and serum creatinine by enriching patient enrollment in clinical trials. In this review, we discuss salient findings on 12 candidate plasma and urine biomarkers and their reported association with CKD. We explore the common pathways of CKD progression and the pathophysiologic processes of tubulointerstitial injury, inflammation, repair, and fibrosis that are potentially classified by specific biomarkers. We describe both pediatric and adult findings and highlight the paucity of pediatric research in CKD progression. It will be important for cohorts with longitudinal follow-up to evaluate these CKD biomarkers for potential use in pediatric clinical trials and routine CKD management. [ABSTRACT FROM AUTHOR]

Background : Children who require surgery for congenital heart disease have increased risk for long-term chronic kidney disease (CKD). Clinical factors as well as urine biomarkers of tubular health and injury may help improve the prognostication of estimated glomerular filtration rate (eGFR) decline. Methods: We enrolled children from 1 month to 18 years old undergoing cardiac surgery in the ASSESS-AKI cohort. We used mixed-effect models to assess the association between urinary biomarkers (log2-transformed uromodulin, NGAL, KIM-1, IL-18, L-FABP) measured 3 months after cardiac surgery and cyanotic heart disease with the rate of eGFR decline at annual in-person visits over 4 years. Results: Of the 117 children enrolled, 30 (24%) had cyanotic heart disease. During 48 months of follow-up, the median eGFR in the subgroup of children with cyanotic heart disease was lower at all study visits as compared with children with acyanotic heart disease (p = 0.01). In the overall cohort, lower levels of both urine uromodulin and IL-18 after discharge were associated with eGFR decline. After adjustment for age, RACHS-1 surgical complexity score, proteinuria, and eGFR at the 3-month study visit, lower concentrations of urine uromodulin and IL-18 were associated with a monthly decline in eGFR (uromodulin β = 0.04 (95% CI: 0.00–0.09; p = 0.07) IL-18 β = 0.07 (95% CI: 0.01–0.13; p = 0.04), ml/min/1.73 m2 per month). Conclusions: At 3 months after cardiac surgery, children with lower urine uromodulin and IL-18 concentrations experienced a significantly faster decline in eGFR. Children with cyanotic heart disease had a lower median eGFR at all time points but did not experience faster eGFR decline. [ABSTRACT FROM AUTHOR]

BACKGROUND. Acute tubulointerstitial nephritis (AIN) is one of the few causes of acute kidney injury with diagnosis-specific treatment options. However, due to the need to obtain a kidney biopsy for histological confirmation, AIN diagnosis can be delayed, missed, or incorrectly assumed. Here, we identify and validate urinary CXCL9, an IFN-γ-induced chemokine involved in lymphocyte chemotaxis, as a diagnostic biomarker for AIN. METHODS. In a prospectively enrolled cohort with pathologist-adjudicated histological diagnoses, termed the discovery cohort, we tested the association of 180 immune proteins measured by an aptamer-based assay with AIN and validated the top protein, CXCL9, using sandwich immunoassay. We externally validated these findings in 2 cohorts with biopsy-confirmed diagnoses, termed the validation cohorts, and examined mRNA expression differences in kidney tissue from patients with AIN and individuals in the control group. RESULTS. In aptamer-based assay, urinary CXCL9 was 7.6-fold higher in patients with AIN than in individuals in the control group (P = 1.23 x 10-5). Urinary CXCL9 measured by sandwich immunoassay was associated with AIN in the discovery cohort (n = 204; 15% AIN) independently of currently available clinical tests for AIN (adjusted odds ratio for highest versus lowest quartile: 6.0 [1.8-20]). Similar findings were noted in external validation cohorts, where CXCL9 had an AUC of 0.94 (0.86-1.00) for AIN diagnosis. CXCL9 mRNA expression was 3.9-fold higher in kidney tissue from patients with AIN (n = 19) compared with individuals in the control group (n = 52; P = 5.8 x 10-6). CONCLUSION. We identified CXCL9 as a diagnostic biomarker for AIN using aptamer-based urine proteomics, confirmed this association using sandwich immunoassays in discovery and external validation cohorts, and observed higher expression of this protein in kidney biopsies from patients with AIN. FUNDING. This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) awards K23DK117065 (DGM), K08DK113281 (KM), R01DK128087 (DGM), R01DK126815 (DGM and LGC), R01DK126477 (KNC), UH3DK114866 (CRP, DGM, and FPW), R01DK130839 (MES), and P30DK079310 (the Yale O'Brien Center). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. [ABSTRACT FROM AUTHOR]

Introduction: Nephrotoxin exposure is significantly associated with acute kidney injury (AKI) development. A standardized list of nephrotoxic medications to surveil and their perceived nephrotoxic potential (NxP) does not exist for non-critically ill patients. Objective: This study generated consensus on the nephrotoxic effect of 195 medications used in the non-intensive care setting. Methods: Potentially nephrotoxic medications were identified through a comprehensive literature search, and 29 participants with nephrology or pharmacist expertise were identified. The primary outcome was NxP by consensus. Participants rated each drug on a scale of 0–3 (not nephrotoxic to definite nephrotoxicity). Group consensus was met if ≥ 75% of responses were one single rating or a combination of two consecutive ratings. If ≥ 50% of responses indicated "unknown" or not used in the non-intensive care setting, the medication was removed for consideration. Medications not meeting consensus for a given round were included in the subsequent round(s). Results: A total of 191 medications were identified in the literature, with 4 medications added after the first round from participants' recommendations. NxP index rating consensus after three rounds was: 14 (7.2%) no NxP in almost all situations (rating 0); 62 (31.8%) unlikely/possibly nephrotoxic (rating 0.5); 21 (10.8%) possibly nephrotoxic (rating 1); 49 (25.1%) possibly/probably nephrotoxic (rating 1.5); 2 (1.0%) probably nephrotoxic (rating 2); 8 (4.1%) probably/definite nephrotoxic (rating 2.5); 0 (0.0%) definitely nephrotoxic (rating 3); and 39 (20.0%) medications were removed from consideration. Conclusions: NxP index rating provides clinical consensus on perceived nephrotoxic medications in the non-intensive care setting and homogeneity for future clinical evaluations and research. [ABSTRACT FROM AUTHOR]

The article focuses on a study which examines the effect of both calcium-based and non-calcium-based phosphate binders on mortality in patients with chronic kidney diseases (CKD). According to the study, International Pharmaceutical Abstracts, Excerpta Medica and Cochrane Central Register of Controlled Trials have been used for published randomized controlled trials (RCTs) and non-RCTs. A table is also presented which depicts that non–calcium-based phosphate binders lowers mortality and CKDs.