A comparison of three commercial platforms for urinary NGAL in critically ill adults.

BACKGROUND: Early biomarkers for acute kidney injury (AKI) diagnosis are needed since an increase in serum creatinine levels is a late marker. Neutrophil gelatinase-associated lipocalin (NGAL) is one of the most promising AKI biomarkers. Prior to routine clinical use, it is necessary to evaluate and validate a high-throughput commercially available method for NGAL detection. The aim of this study was to do an independent validation and comparison of the analytical performance of three different commercially available urine NGAL (uNGAL) assays. METHODS: Urine samples (n=110) were obtained from various patient groups with and without AKI. All urine samples were processed using Architect NGAL assay, Siemens Advia® 2400 NGAL test, and Siemens Dimension Vista® NGAL Test™, based on the three different platforms. RESULTS: Overall, there was good agreement among the three assays: Spearman's rank correlation coefficient between Architect and Vista was 0.989 (95% confidence interval [CI], 0.983-0.993), between Architect and Advia, 0.962 (95% CI, 0.937-0.977), between Vista and Advia 2400, 0.975 (95% CI, 0.961-0.984). We observed a negative bias of Architect compared with the other assays: comparing Architect to Vista, the mean bias was -55.7 ng/mL (95% CI, -74.3 to -37.0 ng/mL); comparing Architect to Advia 2400, the mean bias was -40.9 ng/mL (95% CI, -56.4 to -25.4 ng/nL). The bias is proportional to the concentration of uNGAL and is more pronounced at higher levels, while irrelevant near the tested cutoff levels of 100 and 190 ng/mL. Comparing Vista and Advia 2400, the mean bias was 10.1 ng/mL (95% CI, 1.5-18.8 ng/mL). Intra-assay imprecision was generally acceptable across all assays; coefficient of variation ranged from 0.8% to 5.3%. CONCLUSIONS: All three methods for uNGAL showed acceptable performance for the tested parameters and are comparable with each other at clinically relevant cutoffs. However, Architect yields lower results than the other two methods, with a bias more pronounced at higher uNGAL concentrations, suggesting additional standardization efforts will likely be necessary to better harmonize the uNGAL methods at various clinically relevant cutoffs.

We Use Permcaths Instead of Peritoneal Catheters for Acute Kidney Injury and Urgent-Start Dialysis.

The rising tide of severe acute kidney injury requiring dialysis (AKI-D) and unplanned dialysis initiation for advanced CKD patients remains a major problem for the nephrology community worldwide. Hemodialysis (HD) through a central venous catheter remains the most common practice for both. Peritoneal dialysis (PD) remains greatly underutilized despite mounting evidence of equipoise with HD for a significant proportion of patients. PD is technically simpler, requires less infrastructure, and costs less. However, the structure of our healthcare system, hospital logistics, and the current state of nephrology training all contribute to the reflexive consult for a central venous catheter. As clinicians, we must ask ourselves if we are doing our patients and our healthcare system a disservice by not offering PD in AKI and urgent-start situations.

Pro-Apoptotic Effects of Plasma from Patients with Cardiorenal Syndrome on Human Tubular Cells.

BACKGROUND: The pathophysiology of Cardiorenal Syndrome Type 1 (CRS1) is widely studied, although the mechanisms by which renal tubular epithelial cells (TECs) cease to proliferate and embark upon terminal differentiation, following the initial insult of heart failure (HF), remain a key target. This study seeks to provide insight into the pathophysiological pathways in CRS1; we evaluated in vitro the effects of CRS1 plasma on TECs. METHODS: We enrolled 40 acute HF patients and 15 controls (CTR) without HF or acute kidney injury (AKI). Ten out of 40 HF patients exhibited AKI at the time of admission for HF or developed AKI during hospitalization and were classified as CRS1. In vitro, cell viability, DNA fragmentation and caspase-3 levels were investigated in TECs incubated with HF, CRS1, and CTR plasma. We assessed inflammatory cytokines and NGAL expression at the gene and protein levels. RESULTS: We observed a marked pro-apoptotic activity and a significantly increased in vitro level of apoptosis in TECs incubated with plasma from CRS1 patients compared to HF and CTR (p < 0.01). In the CRS1 group, the mRNA expression of IL-6, IL-18 and NGAL resulted significantly higher in TECs incubated with CRS1 plasma compared with those incubated with plasma from HF and CTR (p < 0.01). IL-6, IL-18, NGAL, and RANTES levels were significantly higher in TECs supernatant incubated with CRS1 plasma compared with HF patients and CTR plasma (p < 0.01). CONCLUSION: In vitro exposure to plasma from CRS1 patients altered the expression profile of TECs characterized by increases in proinflammatory mediators, release of tubular damage markers, and apoptosis.

Understanding acute kidney injury in low resource settings: a step forward.

Attention has recently been focused on addressing the problem of acute kidney injury in both the developed and developing world. Little information is actually available on the incidence and management of AKI in low resource settings. Thus, the paper by Bagasha in the current issue of BMC Nephrology makes an important contribution to our understanding of this serious and potentially remediable problem.

New trends in polymyxin B hemoperfusion: from 2006 to 2013.

Endotoxin, one of the principal components on the outer membrane of Gram-negative bacteria, is considered a key and early component in the pathogenesis of sepsis. Polymyxin B bound to polystyrene fibers (PMX) is a medical device capable of removing circulating endotoxin by adsorption. The most comprehensive analysis to date of clinical experience with this device remains a meta-analysis of 28 studies between 1998 and 2006. This showed that PMX hemoperfusion was associated with improved blood pressure and a reduction in dopamine dose, improved PaO2/FiO2 ratio and lower mortality. Since this meta-analysis, over 50 additional studies on PMX have been published. The majority are observational, with small sample sizes. Notable among the newer studies is the increasing interest in the use of PMX therapy in interstitial pneumonias and idiopathic pulmonary fibrosis, as well as in longer treatment duration and earlier initiation of PMX therapy in an attempt to further improve clinical outcomes. These observational data highlight important aspects of PMX therapy worthy of more rigorous investigation in future studies.

Neutrophil gelatinase-associated lipocalin: ready for routine clinical use? An international perspective.

Acute kidney injury (AKI) remains a challenge in terms of diagnosis and classification, its morbidity and mortality remaining high in the face of improving clinical protocols. Current clinical criteria use serum creatinine (sCr) and urine output to classify patients. Ongoing research has identified novel biomarkers that may improve the speed and accuracy of patient evaluation and prognostication, yet the route from basic science to clinical practice remains poorly paved. International evidence supporting the use of plasma neutrophil gelatinase-associated lipocalin (NGAL) as a valuable biomarker of AKI and chronic kidney disease (CKD) for a number of clinical scenarios was presented at the 31st International Vicenza Course on Critical Care Nephrology, and these data are detailed in this review. NGAL was shown to be highly useful alongside sCr, urinary output, and other biomarkers in assessing kidney injury; in patient stratification and continuous renal replacement therapy (CRRT) selection in paediatric AKI; in assessing kidney injury in conjunction with sCr in sepsis; in guiding resuscitation protocols in conjunction with brain natriuretic peptide in burn patients; as an early biomarker of delayed graft function and calcineurin inhibitor nephrotoxicity in kidney transplantation from extended criteria donors; as a biomarker of cardiovascular disease and heart failure, and in guiding CRRT selection in the intensive care unit and emergency department. While some applications require further clarification by way of larger randomised controlled trials, NGAL nevertheless demonstrates promise as an independent biological marker with the potential to improve earlier diagnosis and better assessment of risk groups in AKI and CKD. This is a critical element in formulating quick and accurate decisions for individual patients, both in acute scenarios and in long-term care, in order to improve patient prognostics and outcomes.

Effects of fluid overload on heart rate variability in chronic kidney disease patients on hemodialysis.

BACKGROUND: While fluid overload (FO) and alterations in the autonomic nervous system (ANS) such as hypersympathetic activity, are known risk factors for cardiovascular morbidity and mortality in patients on chronic hemodialysis (HD), their relationship has not been thoroughly studied. METHODS: In this observational study involving 69 patients on chronic HD, FO was assessed by whole body bioimpedance measurements before the midweek HD session and ANS activity reflected by Heart Rate Variability (HRV) was measured using 24-hour Holter electrocardiogram recordings starting before the same HD treatment. In total, 13 different HRV indices were analyzed, comprising a mixture of time domain, frequency domain and complexity parameters. A correlation analysis was performed between the HRV indices and hydration status indices. Successively, patients were retrospectively assigned to a high FO (H, FO > 2.5 L) or low FO (L, FO ≤ 2.5 L) group and these were further compared also after stratification by diabetes mellitus. Finally, a small number of patients without diabetes with significant and persistent FO were followed up for 3 months post-study to investigate how normalization of fluid status affects HRV. RESULTS: SDANN, VLF, LZC and HF% parameters significantly correlate with FO (correlation coefficients were respectively r = -0.40, r = -0.37, r = -0.28 and r = 0.26, p-value < 0.05). Furthermore, LF% and LF/HF were inversely correlated with hydration status (correlation coefficients were respectively r = -0.31 and r = -0.33, p-value < 0.05). These results indicate an association between FO and reduced HRV, higher parasympathetic activation and reduced sympathetic response to the HD session. Indeed, group H tended to have lower values of SDANN, VLF and LZC, and higher values of HF% than patients in the L group. Finally, there was a trend towards lower LF% measured during the last 30 minutes of HD for the H group versus the L group. Reduction in FO achieved over 3 months by implementation of a strict fluid management plan resulted in an increase of HRV. CONCLUSIONS: Our results suggest that depressed HRV is associated with fluid overload and that normalization of hydration status is accompanied by improved HRV.

High-resolution melt as a screening method in autosomal dominant polycystic kidney disease (ADPKD).

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is an inherited condition caused by PKD1 and PKD2 mutations. Complete analysis of both genes is typically required in each patient. In this study, we explored the utility of High-Resolution Melt (HRM) as a tool for mutation analysis of the PKD2 gene in ADPKD families. METHODS: HRM is a mismatch-detection method based on the difference of fluorescence absorbance behavior during the melting of the DNA double strand to denatured single strands in a mutant sample as compared to a reference control. Our families were previously screened by linkage analysis. Subsequently, HRM was used to characterize PKD2-linked families. Amplicons that produced an overlapping profile sample versus wild-type control were not further evaluated, while those amplicons with profile deviated from the control were consequently sequenced. RESULTS: We analyzed 16 PKD2-linked families by HRM analysis. We observed ten different variations: six single-nucleotide polymorphisms and four mutations. The mutations detected by HRM and confirmed by sequencing were as follows: 1158T>A, 2159delA, 2224C>T, and 2533C>T. In particular, the same haplotype block and nonsense mutation 2533C>T was found in 8 of 16 families, so we suggested the presence of a founder effect in our province. CONCLUSIONS: We have developed a strategy for rapid mutation analysis of the PKD2 gene in ADPKD families, which utilizes an HRM-based prescreening followed by direct sequencing of amplicons with abnormal profiles. This is a simple and good technique for PKD2 genotyping and may significantly reduce the time and cost for diagnosis in ADPKD.

Fluid balance and urine volume are independent predictors of mortality in acute kidney injury.

INTRODUCTION: In ICUs, both fluid overload and oliguria are common complications associated with increased mortality among critically ill patients, particularly in acute kidney injury (AKI). Although fluid overload is an expected complication of oliguria, it remains unclear whether their effects on mortality are independent of each other. The aim of this study is to evaluate the impact of both fluid balance and urine volume on outcomes and determine whether they behave as independent predictors of mortality in adult ICU patients with AKI. METHODS: We performed a secondary analysis of data from a multicenter, prospective cohort study in 10 Italian ICUs. AKI was defined by renal sequential organ failure assessment (SOFA) score (creatinine >3.5 mg/dL or urine output (UO) <500 mL/d). Oliguria was defined as a UO <500 mL/d. Mean fluid balance (MFB) and mean urine volume (MUV) were calculated as the arithmetic mean of all daily values. Use of diuretics was noted daily. To assess the impact of MFB and MUV on mortality of AKI patients, multivariate analysis was performed by Cox regression. RESULTS: Of the 601 included patients, 132 had AKI during their ICU stay and the mortality in this group was 50%. Non-surviving AKI patients had higher MFB (1.31 ± 1.24 versus 0.17 ± 0.72 L/day; P <0.001) and lower MUV (1.28 ± 0.90 versus 2.35 ± 0.98 L/day; P <0.001) as compared to survivors. In the multivariate analysis, MFB (adjusted hazard ratio (HR) 1.67 per L/day, 95%CI 1.33 to 2.09; <0.001) and MUV (adjusted HR 0.47 per L/day, 95%CI 0.33 to 0.67; <0.001) remained independent risk factors for 28-day mortality after adjustment for age, gender, diabetes, hypertension, diuretic use, non-renal SOFA and sepsis. Diuretic use was associated with better survival in this population (adjusted HR 0.25, 95%CI 0.12 to 0.52; <0.001). CONCLUSIONS: In this multicenter ICU study, a higher fluid balance and a lower urine volume were both important factors associated with 28-day mortality of AKI patients.

Extracorporeal therapies in sepsis.

The treatment of sepsis is an ongoing challenge for clinicians; despite the wide choice of effective antibiotics to treat infection, sepsis remains the leading cause of morbidity and mortality for patients admitted to an intensive care unit. Dysregulation of the immune response is now recognized to be a key factor in multiple organ dysfunction, yet our therapy for inflammation remains ineffective. It has been advocated for more than a decade that cytokine reduction in blood compartment could lead to a reduction in mortality in sepsis. Over the years, multiple extracorporeal techniques have evolved, with the intent of influencing the circulating levels of inflammatory mediators like cytokines and chemokines, the complement system, as well as factors of the coagulation system. These include high-volume hemofiltration, use of high cutoff membranes, and systems based on adsorption, such as coupled plasma filtration adsorption and the polymyxin-B column. In addition, new experimental systems that utilize human phagocytic cells and immobilized antibodies for targeted immunomodulation have emerged. In the context of limited resources and growing expansion in the availability of technologies, a better understanding of these therapies is required before they can be properly integrated into standard clinical practice in the hope of influencing major clinical outcomes. In this article, we will provide a concise overview of selected extracorporeal modalities currently in clinical use and briefly introduce some new promising techniques for sepsis.

Genomics and biological activity of neutrophil gelatinase-associated lipocalin in several clinical settings.

Recent literature has shown that neutrophil gelatinase-associated lipocalin (NGAL) is one of the most interesting and promising biomarkers in case of acute kidney injury. However, several studies indicated that this protein may be applied beyond the boundaries of renal pathophysiology and may be used in other pathophysiological settings since it is also expressed in neutrophils, and respiratory, bowel and prostate epithelia. In this review, we report NGAL genomics and biology and its possible use in several clinical settings. In particular, we review the genomic organization of the NGAL gene, the lipocalin family structure, the interaction between NGAL and ligands, and the induction and expression of NGAL in different conditions.

Fluid management in the intensive care unit: bioelectrical impedance vector analysis as a tool to assess hydration status and optimal fluid balance in critically ill patients.

BACKGROUND: Fluid balance disorders are a relevant risk factor for morbidity and mortality in critically ill patients. Volume assessment in the intensive care unit (ICU) is thus of great importance, but there are currently few methods to obtain an accurate and timely assessment of hydration status. Our aim was to evaluate the hydration status of ICU patients via bioelectric impedance vector analysis (BIVA) and to investigate the relationship between hydration and mortality. METHODS: We evaluated 280 BIVA measurements of 64 patients performed daily in the 5 days following their ICU admission. The observation period ranged from a minimum of 72 h up to a maximum of 120 h. We observed the evolution of the hydration status during the ICU stay in this population, and analyzed the relationship between mean and maximum hydration reached and mortality--both in the ICU and at 60 days--using logistic regression. RESULTS: A state of overhydration was observed in the majority of patients (70%) on admission, which persisted during the ICU stay. Patients who required continuous renal replacement therapy (CRRT) were more likely to be overhydrated starting from the 2nd day of observation. Logistic regression showed a strong and significant correlation between mean/maximum hydration reached and mortality, both independently and correcting for severity of prognosis. CONCLUSIONS: Fluid overload measured by BIVA is a frequent condition in critically ill patients--whether or not they undergo CRRT--and a significant predictor of mortality. Hence, hydration status should be considered as an additional prognosticator in the clinical management of the critically ill patient. KEY MESSAGES: (i) On the day of ICU admittance, patients showed a marked tendency to overhydration (>70% of total). This tendency was more pronounced in patients on CRRT. (ii) Hyperhydration persisted during the ICU stay. Patients who underwent CRRT showed significantly higher hyperhydration from the 2nd day of hospitalization. (iii) Nonsurvivors showed worse hyperhydration patterns in comparison to survivors in logistic univariate analysis (p < 0.05). This relationship between hydration and mortality is confirmed even when controlling for the effect of a worse prognosis approximated by any of three ICU scoring systems (APACHE II, SAPS II and SOFA). Mean and maximum hydration levels present a stronger correlation with mortality than with mean and maximum cumulative fluid balance reached during the observation period.

Neutrophil gelatinase-associated lipocalin as a biomarker of cardiovascular disease: a systematic review.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker of acute kidney injury (AKI). Recently, elevated NGAL levels have also been reported in heart failure, coronary heart disease, and stroke. Other studies demonstrate that NGAL is upregulated in failing myocardium and in atherosclerotic plaque. Our aim was to synthesize the current evidence on NGAL and cardiovascular disease (CVD), and to clarify the prognostic significance of systemic NGAL levels in CVD. METHODS: We performed a systematic review to identify experimental and human studies on NGAL and CVD. We excluded articles which specifically dealt with AKI or renal endpoints. RESULTS: We identified 22 studies, including both animal and human data. NGAL is highly expressed in the heart, both in failing myocardium and myocarditis, and is also expressed in atherosclerotic plaques. Areas of co-localization of NGAL and matrix metalloproteinase (MMP)-9 exhibited increased MMP-9 proteolytic activity. Systemic NGAL levels correlated with renal function and severity of CVD in several, but not all, studies. An association between elevated systemic NGAL levels and clinical outcomes (e.g., death, hospital readmissions) were reported in six CVD studies, but these had limited adjustment for potential confounders. CONCLUSIONS: There is ample literature to support a putative role of NGAL in the pathophysiology of CVD, but at present there is insufficient data regarding the clinical utility of systemic NGAL levels in the management of CVD. Available evidence regarding NGAL as a predictor of outcomes in CVD is very limited.

Extracorporeal carbon dioxide removal: the future of lung support lies in the history.

Extracorporeal organ support in patients with dysfunction of vital organs like the kidney, heart, and liver has proven helpful in bridging the patients to recovery or more definitive therapy. Mechanical ventilation in patients with respiratory failure, although indispensable, has been associated with worsening injury to the lungs, termed ventilator-induced lung injury. Application of lung-protective ventilation strategies are limited by inevitable hypercapnia and hypercapnic acidosis. Various alternative extracorporeal strategies, proposed more than 30 years ago, to combat hypercapnia are now more readily available. In particular, the venovenous approach to effective carbon dioxide removal, which involves minimal invasiveness comparable to renal replacement therapy, appears to be very promising. The clinical applications of these extracorporeal carbon dioxide removal therapies may extend beyond just lung protection in ventilated patients. This article summarizes the rationale, technology and clinical application of various extracorporeal lung assist techniques available for clinical use, and some of the future perspectives in the field.

[Contrast-induced nephropathy: the VIKISAFE study group statement]. / Nefropatia da mezzo di contrasto: risoluzioni del gruppo di studio VIKISAFE (VIsipaque KIdney SAfety efFEct).

Contrast-induced nephropathy (CIN) has undergone a significant evolution over the years in terms of epidemiology and diagnostic criteria. At present it is defined as CI-AKI (contrast-induced acute kidney injury) and represents a pathologically relevant event for different disciplines. Thus, a multidisciplinary approach is needed to propose and deploy a common strategy to reduce the incidence of CI-AKI. It seems that the use of isoosmolar non-ionic contrast media such as iodixanol can reduce the nephrotoxic effects. However, since these - still controversial - results have been obtained using various diagnostic criteria, they are difficult to compare and pool together. Common criteria are therefore required. The term acute renal failure has been replaced by acute kidney injury (AKI). Thanks to consensus groups such as ADQI (Acute Dialysis Quality Initiative) and AKIN (Acute Kidney Injury Network) and the development of guidelines by KDIGO, the diagnostic criteria for AKI are well defined. Nevertheless, the possibility to utilize new biomarkers of structural kidney damage such as neutrophil gelatinase-associated lipocalin (NGAL) or cystatin C has introduced the concept that AKI may be diagnosed even in the absence of creatinine elevation or decreased urine output. A re-evaluation of the epidemiology of CI-AKI based on new diagnostic criteria is required. In this paper the results of a collaborative multidisciplinary study group are reported from the perspective of different disciplines including nephrology, cardiology, radiology and pharmacology. The findings in a cohort of cardiac patients undergoing imaging procedures using exclusively the isoosmolar non-ionic contrast medium iodixanol are evaluated according to the RIFLE/AKIN criteria.

[Type 1 cardiorenal syndrome and its possible pathophysiological mechanisms]. / Sindrome cardiorenale di tipo 1: possibili meccanismi patofisiologici alla base di questa sindrome.

Cardiorenal syndrome (CRS) type 1, consisting of acute cardiac events leading to acute kidney injury (AKI), is characterized by multiple factors and its pathophysiology is very complex. Given the circulating nature of many inflammatory mediators, it is tempting to examine the immune-mediated mechanism as a mediator of organ crosstalk. In this pilot study, we examined the possible role of immune-mediated mechanisms in the pathogenesis of this syndrome. We enrolled 12 patients with acute heart failure (AHF), 7 patients with type 1 CRS, and 5 healthy volunteers. EDTA plasma samples from the 3 groups were incubated with a monocyte cell line (U937) and cell apoptosis was subsequently evaluated by different methods. In addition, quantitative determination of TNF-alpha, IL-6 and IL-18 production in the supernatants was performed by ELISA. In U937 cells treated with type 1 CRS plasma, the results showed DNA ladder formation with different molecular weight fractions, suggesting the presence of apoptotic events. In fact, quantitative analysis of apoptosis and caspase-3 levels showed significantly higher apoptosis rates in cells incubated with plasma from patients with type 1 CRS (p<0.05). TNF-alpha levels in the supernatants were significantly elevated in both the AHF and type 1 CRS groups compared with control subjects (p<0.05). Furthermore, in patients with type 1 CRS the levels of the proinflammatory cytokines IL-6 and IL-18 were significantly higher than in AHF patients and the control group (p<0.05). This pilot study explores the premise of an immune-mediated process in the pathophysiology of type 1 CRS. These preliminary findings suggest the presence of defective regulation of apoptosis in patients with this syndrome and the involvement of an immune-mediated mechanism in its pathogenesis. Furthermore, inflammatory pathways seem to play a central role in organ crosstalk and may be fundamental to distant organ damage.

Management and monitoring of haemodynamic complications in acute heart failure.

The pathophysiology of acute heart failure syndromes (AHFS), defined as a change or worsening in heart failure symptoms and signs, is complex. The variety of adverse neurohormonal adaptations includes increased levels of plasma renin, aldosterone and angiotensin II, all responsible for cardio-renal dysfunction. In fact, such alterations result in an array of clinical changes that include abnormal haemodynamics, altered ventricular filling pressures, pathological neurohormonal responses, leading to fluid overload, congestion and ultimately heart failure symptoms. Clinical pictures can be various: in spite of a usual improvement in dyspnoea, little weight change and significant morbidity are generally observed during hospitalization. Short-term outcomes are characterized by a high 60-day re-hospitalization and high mortality rates; apparently, both can be predicted from pre-discharge characteristics. The most frequently used treatments for AHF care include diuretics, inotropic agents, and vasodilator/vasoactive agents; however, the final therapeutic strategy is often individualized. Diuretics are currently the most used agents, but resistance to diuretic therapy is common. In addition, several studies have demonstrated that aggressive diuresis can contribute to reduced renal function, and high doses of diuretics have been associated with increased morbidity and mortality. Many patients with AHFS also suffer from acute or from chronic renal dysfunction (cardio-renal syndromes type 1 and 2, respectively), which further complicate the outcomes and treatment strategies. A personalized patient evaluation of the combined heart and kidney functions is advised to implement the best possible multidisciplinary diagnostic and therapeutic approach.

Epidemiology and outcome of the cardio-renal syndrome.

Cardiac and kidney disease are common, increasingly encountered and often co-exist. Recently, the Acute Dialysis Quality Initiative (ADQI) Working Group convened a consensus conference to develop a classification scheme for the CRS and for five discrete subtypes. These CRS subtypes likely share pathophysiologic mechanisms, however, also have distinguishing clinical features, in terms of precipitating events, risk identification, natural history and outcomes. Knowledge of the epidemiology of heart-kidney interaction stratified by the proposed CRS subtypes is increasingly important for understanding the overall burden of disease for each CRS subtype, along with associated morbidity, mortality and health resource utilization. Likewise, an understanding of the epidemiology of CRS is necessary for characterizing whether there exists important knowledge gaps and to aid the in the design of clinical studies. In the most recent European and American guidelines for heart failure management, acute kidney injury and dysfunction were considered an index of poor prognosis. Paradoxically, however, in many randomized trials of interventions for patients with heart failure, those with kidney injury or dysfunction are often excluded. This review will provide a summary of the epidemiology of the cardio-renal syndrome and its subtypes.

Laboratory parameters of cardiac and kidney dysfunction in cardio-renal syndromes.

"Cardio-Renal Syndromes" (CRS) are disorders of the heart and kidneys in which acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. The pathophysiology of CRS is complex, and there is accumulating evidence that various novel biomarkers are useful for diagnosis, prognostication, and risk stratification in patients with heart failure and chronic kidney disease (CRS). When both the heart failure (HF) and CKD occur together, it is important to have biomarkers that are able to risk stratify patients by looking at both their heart and kidney aspects. There are some promising newer renal biomarkers that may contribute to a better evaluation and prediction of prognosis in CRS patients. Most of the renal biomarkers studies in CRS have been performed in the setting of cardiac surgery, acute coronary syndrome (ACS), HF or after exposure to radiocontrast media in diagnostic and/or therapeutic percutaneous coronary procedures. Natriuretic peptides (NPs) have been validated as an important cardiac biomarker for risk stratification and prognostication in HF patients with or without CKD. However, the best cutoff values for each stage of CKD, including those on renal replacement therapy, are yet to be ascertained. In this context, it is likely that panels of multiple biomarkers will be needed for optimal evaluation, risk stratification, timely treatment initiation, and follow-up of patients with CRS.

Biomarkers in kidney and heart disease.

There is much symptomatic similarity between acute kidney disease and acute heart disease. Both may present with shortness of breath and chest discomfort, and thus it is not surprising that biomarkers of acute myocardial and renal disease often coexist in many physicians' diagnostic work-up schedules. In this review we explore the similarities and differences between current and future tests of myocardial and renal injury and function, with particular emphasis on the diagnostic utility of currently available biomarkers to assist with the diagnosis of cardiorenal syndromes. Imaging studies have not traditionally been viewed as clinical biomarkers, but as tests of structure and function; they contribute to the diagnostic process, and we believe that they should be considered alongside more traditional biomarkers such as blood and urine measurements of circulating proteins and metabolites. We discuss the place of natriuretic peptides, novel tests of kidney damage as well as kidney function and conclude with a discussion of their place in guiding future research studies whose goals must include better characterization of the degree of dysfunction imposed on one organ system by failure of the other.