The use of peritoneal dialysis in heart failure: A systematic review.

Heart failure (HF) is a major cause of morbidity and mortality. Extracorporeal (EC) therapy, including ultrafiltration (UF) and haemodialysis (HD), peritoneal dialysis (PD) and peritoneal ultrafiltration (PUF) are potential therapeutic options in diuretic-resistant states. This systematic review assessed outcomes of PD and compared the effects of PD to EC. A comprehensive search of major databases from 1966 to 2017 for studies utilising PD (or PUF) in diuretic-resistant HF was conducted, excluding studies involving patients with end-stage kidney disease. Data were extracted and combined using a random-effects model, expressed as odds ratio (OR). Thirty-one studies (n = 902) were identified from 3195 citations. None were randomised trials. Survival was variable (0-100%) with a wide follow-up duration (36 h-10 years). With follow-up > 1 year, the overall mortality was 48.3%. Only four studies compared PD with EC. Survival was 42.1% with PD and 45.0% with EC; the pooled effect did not favour either (OR 0.80; 95% confidence interval (CI): 0.24-2.69; p = 0.710). Studies on PD in patients with HF reported several benefits. Left ventricular ejection fraction (LVEF) improved after PD (OR 3.76, 95%CI: 2.24-5.27; p < 0.001). Seven of nine studies saw LVEF increase by > 10%. Twenty-one studies reported the New York Heart Association status and 40-100% of the patients improved by ≥ 1 grade. Nine of 10 studies reported reductions in hospitalisation frequency and/or duration. When treated with PD, HF patients had fewer symptoms, lower hospital admissions and duration compared to diuretic therapy. However, there is inadequate evidence comparing PD versus UF or HD. Further studies comparing these modalities in diuretic-resistant HF should be conducted.

Toward Precision Medicine in the Cardiorenal Syndrome.

Although the field of oncology has made significant steps toward individualized precision medicine, cardiology and nephrology still often use a "one size fits all" approach. This applies to the intersection of the heart-kidney interaction and the cardiorenal syndrome as well. Recent studies have shown that the prognostic implications of worsening renal function (WRF) in acute heart failure are variable; thus, there is a need to differentiate the implications of WRF to better guide precise care. This may best be performed with biomarkers that can give the clinician a real-time evaluation of the physiologic state at the time of developing WRF. This review will summarize current cardiac and renal biomarkers and their status in the evaluation of cardiorenal syndrome. Although we have made progress in our understanding of this syndrome, further investigation is needed to bring precision medicine into routine clinical practice for the care of patients with cardiorenal syndrome.

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.

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.

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.

Promoting Kidney Function Recovery in Patients with AKI Requiring RRT.

AKI requiring RRT is associated with high mortality, morbidity, and long-term consequences, including CKD and ESRD. Many patients never recover kidney function; in others, kidney function improves over a period of many weeks or months. Methodologic constraints of the available literature limit our understanding of the recovery process and hamper adequate intervention. Current management strategies have focused on acute care and short-term mortality, but new data indicate that long-term consequences of AKI requiring RRT are substantial. Promotion of kidney function recovery is a neglected focus of research and intervention. This lack of emphasis on recovery is illustrated by the relative paucity of research in this area and by the lack of demonstrated effective management strategies. In this article the epidemiologic implications of kidney recovery after AKI requiring RRT are discussed, the available literature and its methodologic constraints are reviewed, and strategies to improve the understanding of factors that affect kidney function recovery are proposed. Measures to promote kidney function recovery are a serious unmet need, with a great potential to improve short- and long-term patient outcomes.

Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study.

PURPOSE: Current reports on acute kidney injury (AKI) in the intensive care unit (ICU) show wide variation in occurrence rate and are limited by study biases such as use of incomplete AKI definition, selected cohorts, or retrospective design. Our aim was to prospectively investigate the occurrence and outcomes of AKI in ICU patients. METHODS: The Acute Kidney Injury-Epidemiologic Prospective Investigation (AKI-EPI) study was an international cross-sectional study performed in 97 centers on patients during the first week of ICU admission. We measured AKI by Kidney Disease: Improving Global Outcomes (KDIGO) criteria, and outcomes at hospital discharge. RESULTS: A total of 1032 ICU patients out of 1802 [57.3%; 95% confidence interval (CI) 55.0-59.6] had AKI. Increasing AKI severity was associated with hospital mortality when adjusted for other variables; odds ratio of stage 1 = 1.679 (95% CI 0.890-3.169; p = 0.109), stage 2 = 2.945 (95% CI 1.382-6.276; p = 0.005), and stage 3 = 6.884 (95% CI 3.876-12.228; p < 0.001). Risk-adjusted rates of AKI and mortality were similar across the world. Patients developing AKI had worse kidney function at hospital discharge with estimated glomerular filtration rate less than 60 mL/min/1.73 m(2) in 47.7% (95% CI 43.6-51.7) versus 14.8% (95% CI 11.9-18.2) in those without AKI, p < 0.001. CONCLUSIONS: This is the first multinational cross-sectional study on the epidemiology of AKI in ICU patients using the complete KDIGO criteria. We found that AKI occurred in more than half of ICU patients. Increasing AKI severity was associated with increased mortality, and AKI patients had worse renal function at the time of hospital discharge. Adjusted risks for AKI and mortality were similar across different continents and regions.

Outpatient Dialysis for Patients with AKI: A Policy Approach to Improving Care.

The rate of AKI requiring dialysis has increased significantly over the past decade in the United States. At the same time, survival from AKI seems to be improving, and thus, more patients with AKI are surviving to discharge while still requiring dialysis. Currently, the options for providing outpatient dialysis in patients with AKI are limited, particularly after a 2012 revised interpretation of the Centers for Medicare and Medicaid Services guidelines, which prohibited Medicare reimbursement for acute dialysis at ESRD facilities. This article provides a historical perspective on outpatient dialysis management of patients with AKI, reviews the current clinical landscape of care for these patients, and highlights key areas of knowledge deficit. Lastly, policy changes that have the opportunity to significantly improve the care of this at-risk population are suggested.

[Plasma NGAL and ADPKD progression]. / Ruolo di NGAL nella progressione dell'insufficienza renale determinata da ADPKD.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease with variable rate of progression. It is associated with inter- and intra-familial variability. Neutrophil gelatinase-associated lipocalin (NGAL) has been implicated in pathological conditions and it is proposed as a biomarker for CKD progression. Our aim was to evaluate whether NGAL could be a good marker for progression of ADPKD, as we hypothesized. ADPKD patients with confirmed mutations (PKD1 n=33; PKD2 n=17) were enrolled and followed in a prospective study. Creatinine (sCr) and NGAL values were measured at baseline and on follow-up. Plasma NGAL was measured by Triage point of care test. CKD progression was defined as 15% decrease in eGFR from baseline to follow-up. Patients were divided into 2 groups based on median baseline NGAL and compared by the Kaplan-Meier curve. We enrolled 50 ADPKD pts (60%M age 41 yrs); mean sCr 1.30.7 mg/dl and median eGFR was 62 mL/min/1.73 m2. NGAL values are inversely correlated with baseline eGFR (r=-0.64, p<0.001). There was weak correlation between baseline NGAL and subsequent change in eGFR (r=0.28, p=0.05). 9/50 of patients had NGAL below limits of detection (60 pg/ml); median NGAL level was 79 pg/ml. At follow-up, 12 patients (24%) had progression as defined. No statistically significant relationship between higher NGAL and ADPKD progression was observed. We did not observe a relationship between NGAL and CKD progression in ADPKD patients; however 18% of patients had undetectable plasma NGAL levels. This raises doubt about the utility of the current NGAL assay as a biomarker for CKD progression in this population.

The forgotten role of central volume in low frequency oscillations of heart rate variability.

The hypothesis that central volume plays a key role in the source of low frequency (LF) oscillations of heart rate variability (HRV) was tested in a population of end stage renal disease patients undergoing conventional hemodialysis (HD) treatment, and thus subject to large fluid shifts and sympathetic activation. Fluid overload (FO) in 58 chronic HD patients was assessed by whole body bioimpedance measurements before the midweek HD session. Heart Rate Variability (HRV) was measured using 24-hour Holter electrocardiogram recordings starting before the same HD treatment. Time domain and frequency domain analyses were performed on HRV signals. Patients were retrospectively classified in three groups according to tertiles of FO normalized to the extracellular water (FO/ECW%). These groups were also compared after stratification by diabetes mellitus. Patients with the low to medium hydration status before the treatment (i.e. 1st and 2nd FO/ECW% tertiles) showed a significant increase in LF power during last 30 min of HD compared to dialysis begin, while no significant change in LF power was seen in the third group (i.e. those with high pre-treatment hydration values). In conclusion, several mechanisms can generate LF oscillations in the cardiovascular system, including baroreflex feedback loops and central oscillators. However, the current results emphasize the role played by the central volume in determining the power of LF oscillations.

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.

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.

Utilization of small changes in serum creatinine with clinical risk factors to assess the risk of AKI in critically lll adults.

BACKGROUND AND OBJECTIVES: Disease biomarkers require appropriate clinical context to be used effectively. Combining clinical risk factors, in addition to small changes in serum creatinine, has been proposed to improve the assessment of AKI. This notion was developed in order to identify the risk of AKI early in a patient's clinical course. We set out to assess the performance of this combination approach. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A secondary analysis of data from a prospective multicenter intensive care unit cohort study (September 2009 to April 2010) was performed. Patients at high risk using this combination approach were defined as an early increase in serum creatinine of 0.1-0.4 mg/dl, depending on number of clinical factors predisposing to AKI. AKI was defined and staged using the Acute Kidney Injury Network criteria. The primary outcome was evolution to severe AKI (Acute Kidney Injury Network stages 2 and 3) within 7 days in the intensive care unit. RESULTS: Of 506 patients, 214 (42.2%) patients had early creatinine elevation and were deemed at high risk for AKI. This group was more likely to subsequently develop the primary endpoint (16.4% versus 1.0% [not at high risk], P<0.001). The sensitivity of this grouping for severe AKI was 92%, the specificity was 62%, the positive predictive value was 16%, and the negative predictive value was 99%. After adjustment for Sequential Organ Failure Assessment score, serum creatinine, and hazard tier for AKI, early creatinine elevation remained an independent predictor for severe AKI (adjusted relative risk, 12.86; 95% confidence interval, 3.52 to 46.97). Addition of early creatinine elevation to the best clinical model improved prediction of the primary outcome (area under the receiver operating characteristic curve increased from 0.75 to 0.83, P<0.001). CONCLUSION: Critically ill patients at high AKI risk, based on the combination of clinical factors and early creatinine elevation, are significantly more likely to develop severe AKI. As initially hypothesized, the high-risk combination group methodology can be used to identify patients at low risk for severe AKI in whom AKI biomarker testing may be expected to have low yield. The high risk combination group methodology could potentially allow clinicians to optimize biomarker use.

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.

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.

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.