Molecular Insights and Novel Approaches toward Individualized Arteriovenous Fistula Care.

The aim of the paper is to summarize the current understanding of the molecular biology of arteriovenous fistula (AVF). It intends to encourage vascular access teams, care providers, and scientists, to explore new molecular tools for assessing the suitability of patients for AVF as vascular access for maintenance hemodialysis (HD). This review also highlights most recent discoveries and may serve as a guide to explore biomarkers and technologies for the assessment of kidney disease patients choosing to start kidney replacement therapy. Objective criteria for AVF eligibility are lacking partly because the underlying physiology of AVF maturation is poorly understood. Several molecular processes during a life cycle of an AVF, even before creation, can be characterized by measuring molecular fingerprints using newest "omics" technologies. In addition to hypothesis-driven strategies, untargeted approaches have the potential to reveal the interplay of hundreds of metabolites, transcripts, proteins, and genes underlying cardiovascular adaptation and vascular access-related adjustments at any given timepoint of a patient with kidney disease. As a result, regular monitoring of modifiable, molecular risk factors together with clinical assessment could help to reduce AVF failure rates, increase patency, and improve long-term outcomes. For the future, identification of vulnerable patients based on the assessment of biological markers of AVF maturation at different stages of the life cycle may aid in individualizing vascular access recommendations.

Long-term outcomes of persistent disease and relapse in primary membranous nephropathy.

BACKGROUND: Primary membranous nephropathy is associated with variable clinical course ranging from spontaneous remission to slow progression to end stage renal failure. Achieving remission confers better renal survival in primary membranous nephropathy (PMN). Longer term outcomes such as patient survival and relapse of active disease remain poorly understood. METHODS: We performed a retrospective study of 128 consecutive adult patients diagnosed with biopsy proven PMN at a single UK centre between 1980 and 2010. These patients were followed prospectively over a median of 128 months. We assessed impact of persistent disease and relapse on Stage 5 chronic kidney disease (CKD-5) and patient survival and present longer term cumulative incidences of different end points. RESULTS: One hundred patients achieved partial remission (PartRem) and 28 patients did not achieve remission (NoRem). Nine per cent of patients achieving first remission developed CKD-5 and 75% of those with NoRem developed CKD-5 [hazard ratio (HR) 0.07, 95% confidence interval 0.03-0.19). Relapse following PartRem occurred in 31 patients (31%) during follow-up and was significantly associated with progression to CKD-5. Progression to CKD-5 was strongly associated with death (47 versus 6%, HR 23.4; P < 0.01). Cumulative incidence at 15 years following first presentation included: death, 14%; CKD-5, 28%; and relapse 40% (in patients who achieved first remission). CONCLUSIONS: Our data strongly suggest that mortality in PMN is seen in patients with disease progression to CKD-5. Achieving remission is strongly associated with improved renal survival after first presentation and following relapse. We suggest that patients who achieve remission should be followed up in longer term, and better strategies to help improve outcomes are needed in clinical practice.

Prospective controlled pilot study of arteriovenous fistula placement using the novel Optiflow device.

OBJECTIVE: Arteriovenous fistula (AVF) maturation failure remains a significant problem with reported early failure rates around 50%. Suboptimal hemodynamics, variable surgical skills, and technique dependency are widely believed to contribute to AVF nonmaturation. The Optiflow (Bioconnect Systems, Ambler, Pa) is a novel anastomotic device placed in situ that has potential for improving hemodynamics and standardizing AVF placement. We report results from a prospective nonrandomized controlled pilot study designed to investigate the safety and performance of the Optiflow. METHODS: Forty-one participants underwent AVF formation using either a 3-mm or 4-mm Optiflow and 39 matched control participants underwent AVF formation using the standard technique at two sites. Patients were observed for 90 days after AVF placement. The primary end point was unassisted maturation, which was defined as an outflow vein with a diameter ≥5 mm and blood flow ≥500 mL/min measured by Doppler ultrasound. The secondary performance end point was unassisted patency, and the primary safety end point was freedom from device-related serious adverse events. RESULTS: Unassisted maturation rates at 14, 42, and 90 days were 76%, 72%, and 68%, respectively, for the Optiflow group and 67%, 68%, and 76%, respectively, in the control group (P = .38, .69, and .47 at 14, 42, and 90 days). There was a trend to earlier maturation (assessed at 14 days) in the 4-mm Optiflow group compared with the control group (P = .059). There were no device-related serious adverse events. CONCLUSIONS: Maturation results for both the Optiflow and control groups were highly favorable compared with historical assisted maturation rates of approximately 50%. The Optiflow appears to be safe and effective in the placement of AVFs, with high maturation rates.

Subcutaneous interstitial pressure and volume characteristics in renal impairment associated with edema.

The kidneys and the interstitial compartment play a vital role in body fluid regulation. The latter may be significantly altered in renal dysfunction, but experimental studies are lacking. To help define this we measured the subcutaneous interstitial pressure, bioimpedance volumes, and edema characteristics in 10 healthy subjects and 21 patients with obvious edema and chronic kidney disease (CKD). Interstitial edema was quantified by the time taken for a medial malleolar thumb pit to refill and termed the edema refill time. Interstitial pressure was significantly raised in CKD compared to healthy subjects. Total body water (TBW), extracellular fluid volume (ECFV), interstitial fluid volume, the ratio of the ECFV to the TBW, and segmental extracellular fluid volume were raised in CKD. The ratio of the ECFV to the TBW and the interstitial fluid volume were the best predictors of interstitial pressure. Significantly higher interstitial pressures were noted in edema of 2 weeks or less duration. A significant nonlinear relationship defined interstitial pressure and interstitial fluid volume. Edema refill time was significantly inversely related to interstitial pressure, interstitial compartment volumes, and edema vintage. Elevated interstitial pressure in CKD with obvious edema is a combined function of accumulated interstitial compartment fluid volumes, edema vintage, and tissue mechanical properties. The edema refill time may represent an important parameter in the clinical assessment of edema, providing additional information about interstitial pathophysiology in patients with CKD and fluid retention.

Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy.

Antibodies to the phospholipase A2 receptor 1 (PLA2R1) have been reported in 70% of cases of idiopathic membranous nephropathy (IMN). The genetic susceptibility of IMN has been accounted for by HLA DQA1 and PLA2R1 genes. Here we retrospectively quantified PLA2R antibodies by ELISA, and genotyped DQ alleles and PLA2R1 single-nucleotide polymorphisms for association with clinical criteria for disease activity at the time of first sample and with outcome over a median total follow-up of 90 months. In 90 prevalent patients with biopsy-proven IMN, anti-PLA2R antibodies were present in 75% of patients with IMN with active disease and were significantly higher than in patients in partial or complete remission at the time of antibody measurement. There was a differential IgG subclass response (4>2>3>1) at an early stage, i.e., within 6 months of biopsy. Levels of PLA2R antibodies were significantly linked to DQA1*05:01 and DQB1*02:01. Survival analysis of patients with IMN showed that PLA2R antibodies are significantly linked with outcome. Thus, high levels of PLA2R antibodies are linked with active disease and a higher risk of declining renal function during follow-up. Future therapeutic trials in IMN should monitor anti-PLA2R, as patients with a high antibody burden may benefit from earlier therapeutic intervention.

Technique survival in home haemodialysis: a composite success rate and its risk predictors in a prospective longitudinal cohort from a tertiary renal network programme.

BACKGROUND: Resurgence of interest in home haemodialysis (HHD) is, in part, due to emerging evidence of the benefits of extended HD regimens, which are most feasibly provided in the home setting. Although specific HHD therapy established at home such as nocturnal HD (NHD) has been reported from individual programmes, little is known about overall HHD success. METHODS: The study included 166 patients who were accepted in the Manchester (UK) HHD training programme through liberal selection criteria. All patients were followed up prospectively until a switch to alternative modality, to include 4528 patient-months of follow-up and about 81 508 HHD sessions during an 8-year period (January 2004-December 2011). Twenty-four patients switched to an alternative modality during the period. Combined technique survival (HHDc) as a composite of training (HHDtr) and at home (HHDhome) was analysed and clinical predictors of HHD modality failure since the commencement of the programme were calculated using Cox regression analysis. Technology-related interruptions to dialysis over a 12-month period and patient-reported reasons for quitting the programme were analysed. RESULTS: Technique survival at 1, 2 and 5 years was 90.2, 87.4, 81.5% (HHDc) and 98.4, 95.4 and 88.9% (HHDhome) when censored for training phase exits, death and transplantation. The combined HHDc modality switch rate is 1 in 192 patient-months of dialysis follow-up. Age >60 years, diabetes, cardiac failure, unit decrease in Hb and increasing score of age-adjusted Charlson--comorbidity index were significantly associated with technique failure. Significant clinical predictors of HHD technique failure in a multivariate model were diabetes (P = 0.002) and cardiac failure (P = 0.05). The majority (61%) switched to an alternative modality for non-medical reasons. The composite of operator error and mechanical breakdown resulting in temporary HHD technique failure was 0.7% per year. CONCLUSIONS: HHD training and technique failure rate are low. Technical errors are infrequent too. Diabetes and cardiac failure are associated with significant risk of technique failure. Although absolute rates are low, training failure is proportionally quite significant, highlighting the importance of reporting the composite technique failure rate (to include early HHD training phase) in HHD programmes.

Development and validation of AI-based triage support algorithms for prevention of intradialytic hypotension.

BACKGROUND: Intradialytic hypotension remains one of the most recurrent complications of dialysis sessions. Inadequate management can lead to adverse outcomes, highlighting the need to develop personalized approaches for the prevention of intradialytic hypotension. Here, we sought to develop and validate two AI-based risk models predicting the occurrence of symptomatic intradialytic hypotension at different time points. METHODS: The models were built using the XGBoost algorithm and they predict the occurrence of intradialytic hypotension in the next dialysis session and in the next month. The initial dataset, obtained from routinely collected data in the EuCliD® Database, was split to perform model derivation, training and validation. Model performance was evaluated by concordance statistic and calibration charts; the importance of features was assessed with the Shapley Additive Explanation (SHAP) methodology. RESULTS: The final dataset included 1,249,813 dialysis sessions, and the incidence rate of intradialytic hypotension was 10.07% (95% CI 10.02-10.13). Our models retained good discrimination (AUC around 0.8) and a suitable calibration yielding to the selection of three classification thresholds identifying four distinct risk groups. Variables providing the most significant impact on risk estimates were blood pressure dynamics and other metrics mirroring hemodynamic instability over time. CONCLUSIONS: Recurrent symptomatic intradialytic hypotension could be reliably and accurately predicted using routinely collected data during dialysis treatment and standard clinical care. Clinical application of these prediction models would allow for personalized risk-based interventions for preventing and managing intradialytic hypotension.

Multitargeted interventions to reduce dialysis-induced systemic stress.

Hemodialysis (HD) is a life-sustaining therapy as well as an intermittent and repetitive stress condition for the patient. In ridding the blood of unwanted substances and excess fluid from the blood, the extracorporeal procedure simultaneously induces persistent physiological changes that adversely affect several organs. Dialysis patients experience this systemic stress condition usually thrice weekly and sometimes more frequently depending on the treatment schedule. Dialysis-induced systemic stress results from multifactorial components that include treatment schedule (i.e. modality, treatment time), hemodynamic management (i.e. ultrafiltration, weight loss), intensity of solute fluxes, osmotic and electrolytic shifts and interaction of blood with components of the extracorporeal circuit. Intradialytic morbidity (i.e. hypovolemia, intradialytic hypotension, hypoxia) is the clinical expression of this systemic stress that may act as a disease modifier, resulting in multiorgan injury and long-term morbidity. Thus, while lifesaving, HD exposes the patient to several systemic stressors, both hemodynamic and non-hemodynamic in origin. In addition, a combination of cardiocirculatory stress, greatly conditioned by the switch from hypervolemia to hypovolemia, hypoxemia and electrolyte changes may create pro-arrhythmogenic conditions. Moreover, contact of blood with components of the extracorporeal circuit directly activate circulating cells (i.e. macrophages-monocytes or platelets) and protein systems (i.e. coagulation, complement, contact phase kallikrein-kinin system), leading to induction of pro-inflammatory cytokines and resulting in chronic low-grade inflammation, further contributing to poor outcomes. The multifactorial, repetitive HD-induced stress that globally reduces tissue perfusion and oxygenation could have deleterious long-term consequences on the functionality of vital organs such as heart, brain, liver and kidney. In this article, we summarize the multisystemic pathophysiological consequences of the main circulatory stress factors. Strategies to mitigate their effects to provide more cardioprotective and personalized dialytic therapies are proposed to reduce the systemic burden of HD.

Development and Validation of a Machine Learning Model Predicting Arteriovenous Fistula Failure in a Large Network of Dialysis Clinics.

Background: Vascular access surveillance of dialysis patients is a challenging task for clinicians. We derived and validated an arteriovenous fistula failure model (AVF-FM) based on machine learning. Methods: The AVF-FM is an XG-Boost algorithm aimed at predicting AVF failure within three months among in-centre dialysis patients. The model was trained in the derivation set (70% of initial cohort) by exploiting the information routinely collected in the Nephrocare European Clinical Database (EuCliD®). Model performance was tested by concordance statistic and calibration charts in the remaining 30% of records. Features importance was computed using the SHAP method. Results: We included 13,369 patients, overall. The Area Under the ROC Curve (AUC-ROC) of AVF-FM was 0.80 (95% CI 0.79-0.81). Model calibration showed excellent representation of observed failure risk. Variables associated with the greatest impact on risk estimates were previous history of AVF complications, followed by access recirculation and other functional parameters including metrics describing temporal pattern of dialysis dose, blood flow, dynamic venous and arterial pressures. Conclusions: The AVF-FM achieved good discrimination and calibration properties by combining routinely collected clinical and sensor data that require no additional effort by healthcare staff. Therefore, it can potentially enable risk-based personalization of AVF surveillance strategies.

Low, rather than High, Body Mass Index Is a Risk Factor for Acute Kidney Injury in Multiethnic Asian Patients: A Retrospective Observational Study.

BACKGROUND: Acute kidney injury (AKI) is common in hospitalised patients. The relationship between body mass index (BMI) and the risk of having AKI for patients in the acute hospital setting is not known, particularly in the Asian population. METHODS: This was a retrospective, single-centre, observational study conducted in Singapore, a multiethnic population. All patients aged ≥21 years and hospitalised from January to December 2013 were recruited. RESULTS: A total of 12,555 patients were eligible for the analysis. A BMI of <18.5 kg/m2 was independently associated with the development of AKI in hospitalised patients (odds ratio (OR): 1.23 [95% confidence interval [CI]: 1.04-1.44, P = 0.01]) but not for overweight and obesity. Subgroup analysis further revealed that underweight patients aged ≥75 and repeated hospitalisation posed a higher risk of AKI (OR: 1.25 [CI: 1.01-1.56], P = 0.04; OR: 1.23 [CI: 1.04-1.44], P = 0.01, resp.). Analyses by interactions between different age groups and BMI using continuous or categorised variables did not affect the overall probability of developing AKI. CONCLUSIONS: Underweight Asian patients are susceptible to AKI in acute hospital settings. Identification of this novel risk factor for AKI allows us to optimise patient care by prevention, early detection, and timely intervention.

A rare anatomic variant of a single-conduit supraclavicular cephalic arch draining into the external jugular vein presenting with recurrent arteriovenous fistula stenosis in a hemodialysis patient.

The cephalic arch is a common location of stenosis, especially in brachiocephalic fistulas. The cephalic arch has a number of anatomic variations. Cephalic arch stenoses are often resistant and have poor primary patency. Here we describe an unusual case of a hemodialysis patient with a single-conduit supraclavicular cephalic arch draining into the external jugular vein presenting with recurrent cephalic arch stenoses and external jugular vein stenosis. In our view, extrinsic compression by the clavicle may contribute to the high rate of recurrence, the lack of complete dilation of even high-pressure balloons, and a theoretically heightened risk of rupture when cutting balloons are used.

Outcomes of a nephrologist-driven tunnelled dialysis catheter insertion service in South East Asia.

INTRODUCTION: Tunnelled dialysis catheters (TDCs) are being increasingly inserted by nephrologists globally but there is limited experience and paucity of published outcomes data from South-East Asia (SEA). This study was conducted to analyse the outcomes of TDC insertion by nephrologists from a single centre in SEA. METHODS: All patients who underwent TDC insertion by nephrologists from October 2013 to June 2016 were included. TDC survival was calculated using Kaplan-Meier survival method. Impact of variables was assessed using Cox proportional hazards model. RESULTS: A total of 344 TDCs were inserted in 274 patients. The most common indication was haemodialysis initiation (60.2%) followed by existing catheter dysfunction (CD) (12.2%), failed vascular access (10.2%) and catheter-related bacteraemia (CRB) (9.9%). Insertion was successful in 97% patients. The most common location was the right internal jugular vein (87%). The cumulative survival for all TDCs inserted, as defined by the time to non-elective removal of a TDC, at 3, 6 and 9 months was 83%, 61%, and 44%, respectively. Median catheter survival was 231 days. Common indications for removal were CD (13.4%) and CRB or suspected infection (12.5%). Common complications were bleeding (8.72%), infection (13.7%) and CD (16.5%). Median time to infection was 103 days. In multivariate analysis, male gender was associated with poor catheter survival, for primary insertions (p = 0.015, HR 0.62) and diabetes was associated with TDC infection (p = 0.024, OR 1.1). CONCLUSIONS: This is one of the first reports of TDC insertion by nephrologists from SEA. Our outcomes compare favourably with those reported in the literature.

Acute arteriovenous access failure: long-term outcomes of endovascular salvage and assessment of co-variates affecting patency.

AIMS: This study reports long-term outcomes after endovascular salvage (EVS) for acute dialysis fistula/graft dysfunction. METHODS: All patients presenting with acute fistula or graft dysfunction, excluding primary failures, referred for endovascular salvage were included in this single-centre prospective study. RESULTS: Altogether, 410 procedures were carried out in 232 patients. Overall, the incidence of thrombosis/occlusion (per patient-year) was 0.12 for fistulae and 0.9 for grafts. The anatomical success rate for EVS was 94% for fistulae and 92% for grafts. Primary patency rates for fistulae at 1, 6, 12, 24 and 36 months were 82, 64, 44, 34 and 26%, respectively, whereas secondary patency rates were 88, 84, 74, 69 and 61%, respectively. Primary patency rates for grafts at 1, 6 and 12 months were 50, 14 and 8%. The overall rate of complications was 6% with no incidence of symptomatic pulmonary embolism. In a Cox regression model, upper-arm location of fistula (HR 1.9, p = 0.04, n = 144) was associated with lower primary patency, whereas the presence of thrombosis was associated lower primary (HR 1.9, p = 0.004, n = 144) and secondary patency (HR 3.7, p < 0.001, n = 144). Aspirin therapy was associated with longer primary patency (HR 0.6, p = 0.02, n = 144) and secondary patency (HR 0.58, p = 0.08, n = 144). CONCLUSION: EVS is effective but longer-term outcomes are poor. Presence of thrombosis portends poor fistula survival and strategies for prevention need attention. Balloon maceration, our preferred declotting technique, is safe and the most cost-effective method. Aspirin therapy for patients presenting with failure of fistulae deserves further investigation.

Medication burden in CKD-5D: impact of dialysis modality and setting.

BACKGROUND: Medication adherence is thought to be around 50% in the general and dialysis population. Reducing the pill burden (PB) reduces regime complexity and can improve adherence. Increased adherence should lead to improvement in treatment outcomes and patient quality of life. There is currently little published data on PB in CKD-5D across dialysis modalities. METHODS: This is a retrospective, single renal network study. All in-centre HD (MHD), peritoneal dialysis (PD) and home HD (HHD) patients were identified in the Greater Manchester East sector renal network. Information collected included age, sex, comorbidities, daily PB, dialysis vintage and adequacy. Data were retrieved from a customized renal database, clinic and discharge letters with cross validation from the general practitioner when needed. RESULTS: Two hundred and thirty-six prevalent dialysis patients were studied. HHD patients had a significantly lower PB (11 ± 7 pills/day) compared with PD and MHD (16 ± 7 pills/day). The HHD patients required fewer BP medications to meet the recommended target. HD setting was the only significant factor for reducing PB. For home therapies (HHD versus PD), weekly Kt/v and serum phosphate were significant factors influencing PB. When comparing all modalities, OR of PB ≥ 15/day for MHD versus HHD was 3.9 and PD versus HHD was 4.9. The influence of HHD is dominant above factors such as comorbidities or clinical variables in reducing PB for MHD. Higher clearances achieved by HHD could explain differences in PB with PD. CONCLUSION: This is the first comparative study of PB across all dialysis modalities and factors that influence it. The PB advantage in HHD may result in greater adherence and might contribute to the outcome benefit often seen with this modality. Higher clearances achieved by HHD could explain differences in PB with PD but the precise reasons for lower PB remain speculative and deserve further research in larger settings.

Arteriovenous fistula creation using the Optiflow™ vascular anastomotic connector: the OPEN (Optiflow PatEncy and MaturatioN) study.

PURPOSE: Arteriovenous fistulas (AVFs) are the preferred form of vascular access for hemodialysis. However, non-maturation and patency are major clinical problems. The Optiflow™ device is an implantable anastomotic connector used to standardize the creation of an AVF. Studies have suggested that the geometry of the anastomosis and experience of the surgeon impact patency and maturation rates. The Optiflow serves as a surgical template whereby the geometry and flow path of the anastomosis are predetermined. This prospective study was intended to evaluate maturation, patency and safety of the Optiflow. METHODS: Forty-one upper arm AVFs were created in 41 end-stage renal disease patients using the Optiflow device at two investigational sites. Patients were followed for 90 days with serial Doppler ultrasounds performed at approximately 14, 42 and 90 days to determine AVF maturation. The primary performance endpoint was unassisted maturation, defined as an outflow vein that was equal to or greater than 5 mm in diameter, and with flow equal to or greater than 500 mL/min without the need for any intervention intended to promote or maintain maturation. The primary safety endpoint was the rate of device-related serious adverse events. RESULTS: Unassisted maturation rates were 76%, 72% and 68% and unassisted patency rates were 93%, 88% and 78%, at 14, 42 and 90 days, respectively. There were no device-related serious adverse events. CONCLUSIONS: The results suggest that the Optiflow is safe for its intended use and could play an important role in enhancing AVF maturation while standardizing the anastomotic technique.

Arteriovenous fistula failure: is there a role for accessory draining vein embolization?

PURPOSE: Arterio-venous fistulae (AVFs) are accepted as the best form of haemodialysis vascular access (VA) but are plagued by high primary failure. Accessory drainage veins (ADVs) may account for up to 40% of these failures. Furthermore, they may also lead to low flow in 'mature' AVFs. METHODS: We analysed the results of 42 patients who underwent endovascular coiling of ADVs at our centre over a 4-year period. RESULTS: Indications were failure to mature in 34%, low flow or cannulation difficulty in 56% and thrombosis in 10% of cases. 95% procedures involved a combination of angioplasty and coiling with only 5% patients having coiling of ADV alone. Forearm AVFs constituted the majority of the cases as opposed to upper arm AVFs (74% vs. 26% respectively). Primary patency at 3, 6, 12, 18 and 24 months was 90%, 87%, 76%, 70% and 55% respectively. Successful dialysis was achieved in 10 of the 14 fistulae that had hitherto failed to mature. Coil migration was observed in 1 patient, which led to fistula occlusion. CONCLUSION: Coil embolisation of ADVs is an effective treatment option for dysfunctional fistulae that can be performed at the same time as angioplasty.

Idiopathic or iatrogenic membranous glomerulonephritis? A case of spironolactone-induced membranous glomerulonephritis.

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults in the UK. In most cases, the aetiology remains unknown, although recent data suggested a clear mechanism of pathogenesis. In approximately a quarter of cases, however, a presumed cause is found, such as systemic lupus nephritis, malignancy, hepatitis B and various drugs. Here, we present a patient who developed MN soon after commencing spironolactone and whose condition persisted for the duration of exposure to the drug only to resolve with cessation of the drug. No cases of spironolactone-induced MN have been reported in the literature previously.