Study protocol of a randomized controlled trial of fistula vs. graft arteriovenous vascular access in older adults with end-stage kidney disease on hemodialysis: the AV access trial.

BACKGROUND: Treatment of end-stage kidney disease (ESKD) with hemodialysis requires surgical creation of an arteriovenous (AV) vascular access-fistula (AVF) or graft (AVG)-to avoid (or limit) the use of a central venous catheter (CVC). AVFs have long been considered the first-line vascular access option, with AVGs as second best. Recent studies have suggested that, in older adults, AVGs may be a better strategy than AVFs. Lacking evidence from well-powered randomized clinical trials, integration of these results into clinical decision making is challenging. The main objective of the AV Access Study is to compare, between the two types of AV access, clinical outcomes that are important to patients, physicians, and policy makers. METHODS: This is a prospective, multicenter, randomized controlled trial in adults ≥ 60 years old receiving chronic hemodialysis via a CVC. Eligible participants must have co-existing cardiovascular disease, peripheral arterial disease, and/or diabetes mellitus; and vascular anatomy suitable for placement of either type of AV access. Participants are randomized, in a 1:1 ratio, to a strategy of AVG or AVF creation. An estimated 262 participants will be recruited across 7 healthcare systems, with average follow-up of 2 years. Questionnaires will be administered at baseline and semi-annually. The primary outcome is the rate of CVC-free days per 100 patient-days. The primary safety outcome is the cumulative incidence of vascular access (CVC or AV access)-related severe infections-defined as access infections that lead to hospitalization or death. Secondary outcomes include access-related healthcare costs and patients' experiences with vascular access care between the two treatment groups. DISCUSSION: In the absence of studies using robust and unbiased research methodology to address vascular access care for hemodialysis patients, clinical decisions are limited to inferences from observational studies. The goal of the AV Access Study is to generate evidence to optimize vascular access care, based on objective, age-specific criteria, while incorporating goals of care and patient preference for vascular access type in clinical decision-making. TRIAL REGISTRATION: This study is being conducted in accordance with the tenets of the Helsinki Declaration, and has been approved by the central institutional review board (IRB) of Wake Forest University Health Sciences (approval number: 00069593) and local IRB of each participating clinical center; and was registered on Nov 27, 2020, at ClinicalTrials.gov (NCT04646226).

Cancer surveillance imaging: Does repeated iodinated contrast exposure impact long-term kidney function?

BACKGROUND: Contrast-induced nephropathy is a well-recognized acute complication in cancer patients, but the long-term effects of repeated contrast exposure are not known. We analyzed the association of the number of contrast-enhanced computed tomography (CECT) examinations and other clinical factors with decline in estimated glomerular filtration rate (eGFR) in colorectal cancer survivors. MATERIALS AND METHODS: We retrospectively queried a prospective surgical colorectal cancer database to identify patients with stage I or II cancer who underwent resection in 2007 - 2013 and were alive for at least 3 years. eGFR was calculated before and 3 years after the surgery with ≥ 20% decline relative to baseline defined as significant and used as the primary outcome. The association of clinical factors with the primary outcome was analyzed using logistic regression. RESULTS: Only 256 patients with the median follow-up of 65 months had sufficient clinical data for analysis. Median eGFR decline at follow-up was 3.0 mL/min/1.73m2 or 4% change from baseline. 47 patients (18%) had ≥ 20% reduction in eGFR, which was not associated with the number of CECT examinations. Multivariable analysis demonstrated that increasing age (OR, 1.03; 95% CI, 1.00 - 1.06), presence of diabetes (OR, 2.33; 95% CI, 1.18 - 4.61), and longer operation time (OR, 1.04; 95% CI, 1.01 - 1.07) were independently associated with a higher likelihood of ≥ 20% eGFR decline at 3 years. CONCLUSION: Older age, diabetes, and longer operating time, but not cumulative contrast exposure were found to be associated with worse long-term renal outcomes following surgical resection in patients with early-stage colorectal cancer who survived 3 years.

Kidney Complications of Immune Checkpoint Inhibitors: A Review.

Immunologic control of malignancy has long been recognized as an important determinant of disease progression. Recent advances in immunology have led to the focus on several mechanisms that can be targeted to achieve tumor suppression. In particular, checkpoint inhibition has evolved in less than a decade to become one of the most important strategies in cancer therapy, with a meaningful improvement in patient survival. Six agents have been approved for clinical use to date and many more are in the industry pipeline. The spectrum of malignancies responsive to immunotherapy ranges from advanced melanoma, for which the first immune checkpoint inhibitor ipilimumab was approved, to Hodgkin lymphoma, non-small cell lung cancer, renal cell carcinoma, and others. Notwithstanding its clinical benefits, checkpoint inhibition carries a risk for significant off-target toxicity stemming from the immune system activation. In this review, we discuss general principles of checkpoint inhibition, mechanisms of toxicity, and kidney complications of the treatment and propose diagnostic and treatment strategies when kidney injury occurs.

Renal cell carcinoma: new insights and challenges for a clinician scientist.

There is a growing recognition of the complex interplay between renal cell cancer (RCC), kidney function, mechanical reduction of nephron mass, and systemic agents targeting the cancer. Earlier detection of RCC and rising life expectancy of cancer survivors places a greater emphasis on preservation of renal function after cancer resection and during systemic therapy. Unique adverse effects associated with RCC drugs not only help reveal cancer pathophysiology but also expand our knowledge of normal cell signaling and metabolism. In this review, we outline our current understanding of RCC biology and treatment, their bidirectional relationship with kidney function, and unmet research needs in this field.

Validating the anatomical landmark technique for bedside tunneled central venous catheter placement in the medical intensive care unit.

BACKGROUND: A non-tunneled dialysis catheter (nTDC) is often the vascular access of choice to initiate dialysis in an intensive care unit (ICU). In the absence of contraindications, if a patient remains dialysis dependent beyond 2-weeks, the options are either to replace the nTDC with another nTDC or convert to a tunneled dialysis catheter (TDC). As a standard of care, TDCs are placed under fluoroscopic guidance. OBJECTIVES: To determine if TDCs and other tunneled central venous catheters (tCVC) can be placed safely using anatomical landmark techniques without the use of fluoroscopy. RESEARCH DESIGN: Subjects that met a predetermined selection criteria underwent placement of tunneled catheters with the use of the anatomical landmark technique. We looked at various outcomes to determine the safety and effectiveness of this technique. SUBJECTS: One hundred eleven TDCs and other tCVCs were placed using the anatomical landmark technique in the intensive care unit. RESULTS: All but one (110/111) of the catheters placed had recommended tip placement confirmed by at least one blinded physician. Major complications encountered were bleeding (two cases), pneumothorax (one case), and line associated blood stream infection (one case). We did find a higher-than-expected rate of "unnecessary procedures" with 18/111 lines placed in patients who did not survive beyond 7 days after placement of the catheter. CONCLUSIONS: Using the anatomical landmark technique for bedside tunneled catheter placement can be an effective approach in the right population.

Evaluation of Cisplatin-Induced Acute Kidney Injury in Patients Co-Prescribed Serotonin Receptor Antagonists: A Retrospective Analysis.

BACKGROUND: Cisplatin is an effective first line therapy for a variety of cancers. Cisplatin is highly emetogenic and resulting volume depletion can contribute to acute kidney injury (AKI). Anti-emetic drugs such as 5-hydroxytryptamine type 3 receptor antagonists (5-HT3RAs) are commonly prescribed to prevent this complication. Preclinical studies suggest first generation 5-HT3RAs may alter the renal clearance and increase cisplatin toxicity. This retrospective study evaluated whether different 5-HT3RAs modify the risk of AKI in patients receiving cisplatin. METHODS: Patients with cancer who received cisplatin between January 1, 2010 and December 31, 2016 were included. Patients over 18 years old with available data for baseline and post-treatment serum creatinine, cisplatin cumulative dose, and administration of 5-HT3RAs including first generation (ondansetron, granisetron, and ramosetron) and second generation (palonosetron) were analyzed. AKI defined as 1.5x increase in serum creatinine. Fisher's exact and Wilcoxon rank-sum tests were used to assess univariable associations between baseline covariates and AKI, and logistic regression for multivariable associations with AKI. RESULTS: Of 8703 patients identified with cisplatin exposure, 6889 were included. A total of 3881 (56.3%) patients received at least one 5-HT3RA, including palonosetron (3750, 54.4%), ondansetron (1399, 20.3%) and granisetron (11, 0.2%). AKI developed in 1666 (24.2%) patients following cisplatin. Patients who received any 5-HT3RAs were less likely to experience AKI as compared to patients that did not (22.6% vs 26.2%, p=0.001). Older age, male gender, African ethnicity, and cumulative cisplatin dose were univariately associated with higher risk for AKI (P<0.001). After adjusting for these variables, use of any of these antiemetic drugs was protective for AKI (OR 0.84, 95% CI: 0.75, 0.94; P= 0.003) with no difference detected between type of 5-HT3RA. CONCLUSION: Nephrotoxicity continues to be a concern following cisplatin therapy. Given its emetogenic nature, use of antiemetic drugs such as 5-HT3RAs can lessen emesis and lower risk of kidney injury. This retrospective analysis supports use of any 5-HT3RAs to lower risk of AKI.

Natural history of tunneled dialysis catheters placed for hemodialysis initiation.

PURPOSE: More than 80% of hemodialysis recipients in the United States initiate hemodialysis with a tunneled dialysis catheter (TDC). Published data on TDC outcomes are based on a case mix of prevalent and incident TDCs. The present study analyzes factors affecting patency and complications of first TDCs placed in a large cohort of incident hemodialysis recipients. MATERIALS AND METHODS: A prospective, computerized vascular access database was retrospectively queried to identify 472 patients receiving a first-ever TDC. Multiple-variable survival analysis was used to identify clinical parameters affecting TDC patency (from placement to nonelective removal) and infection (from placement to first episode of catheter-related bacteremia [CRB]). RESULTS: The median patency of all TDCs was 202 days. Left-sided placement of TDCs was the only variable associated with inferior TDC patency (hazard ratio, 1.98; 95% confidence interval, 1.39-2.81; P < .0001). The 6-month TDC patency rate was 37% for left internal jugular vein (LIJV) catheters, versus 54% for right internal jugular vein (RIJV) catheters. The 1-year patency rate was 6% for LIJV catheters, versus 35% for RIJV catheters. Catheter patency was not associated with patient age, sex, race, hypertension, diabetes, coronary artery disease, peripheral vascular disease, cerebrovascular disease, or heart failure. The median time to the first episode of CRB was 163 days. None of the clinical variables was associated with TDC infection. CONCLUSIONS: TDCs are plagued by high rates of infection. RIJV TDCs should be used preferentially to maximize catheter patency.

Global hemodialysis vascular access care: Three decades of evolution.

The development of vascular access for hemodialysis has come a long way since 1943 when the first hemodialysis treatment was performed in humans by connecting an artery and vein using an external glass canula. Since then, vascular access care has evolved robustly through contributions from numerous countries and professional nephrology societies, worldwide. To understand the global distribution and contribution of different specialties to medical literature on dialysis vascular access care, we performed a literature search from 1991 to 2021 and identified 2768 articles from 74 countries. The majority of publications originated from the United States (41.5%), followed by China (5.1%) and the United Kingdom (4.6%). Our search results comprise of observational studies (43%), case reports/series (27%), review articles (16.5%) and clinical trials (12%). A large proportion of articles were published in Nephrology journals (49%), followed by General Medicine (14%), Surgery (10%), Vascular Medicine (8%), and Interventional Radiology journals (4%). With the introduction of interventional nephrology, nephrologists will be able to assume the majority of the responsibility for dialysis vascular access care and above all maintain a close interdisciplinary collaboration with other specialties to provide optimum patient care. In this review article, we discuss the history, evolving knowledge, challenges, educational opportunities, and future directions of dialysis vascular access care, worldwide.

Association of hemodialysis central venous catheter use with ipsilateral arteriovenous vascular access survival.

BACKGROUND: Central venous catheters frequently are used for hemodialysis vascular access while patients await placement and maturation of an arteriovenous fistula or graft. Catheters may cause central vein stenosis, which can adversely affect vascular access outcomes. We compared vascular access outcomes in patients with a history of ipsilateral and contralateral dialysis catheters. STUDY DESIGN: Retrospective analysis of a prospective computerized vascular access database. SETTING & PARTICIPANTS: Patients at a large medical center who initiated hemodialysis therapy with a catheter and subsequently received a fistula (n = 233) or graft (n = 89). PREDICTOR: History of central venous catheter placement ipsilateral versus contralateral to the arteriovenous fistula or graft. OUTCOME & MEASUREMENTS: Primary access failure (access never suitable for dialysis) and cumulative access survival (time from successful cannulation until permanent access failure). RESULTS: For patients receiving a fistula, the primary failure rate was similar for those with ipsilateral and contralateral catheters (50% vs 53%; HR, 0.94; 95% CI, 0.71-1.26; P = 0.7), and time to fistula maturation was similar (101 ± 41 vs 107 ± 39 days; P = 0.5). However, cumulative fistula survival was inferior in patients with ipsilateral catheters (HR, 2.48; 95% CI, 1.33-7.33; P = 0.009). For patients receiving a graft, the primary failure rate was similar for those with ipsilateral and contralateral catheters (35% vs 38%; HR, 0.92; 95% CI, 0.49-1.73; P = 0.8), but cumulative graft survival tended to be shorter with ipsilateral catheters (HR, 2.04; 95% CI, 0.92-5.38; P = 0.07). LIMITATIONS: Retrospective analysis, single medical center. CONCLUSIONS: The primary failure rate of fistulas and grafts is not affected by the presence of an ipsilateral catheter. However, cumulative access survival is inferior in patients with prior ipsilateral catheters. Avoidance of ipsilateral catheters may improve long-term vascular access survival.

Arteriovenous graft placement in predialysis patients: a potential catheter-sparing strategy.

BACKGROUND: When predialysis patients are deemed unsuitable candidates for an arteriovenous fistula, current guidelines recommend waiting until just before or after initiation of dialysis therapy before placing a graft. This strategy may increase catheter use when these patients start dialysis therapy. We compared the outcomes of patients whose grafts were placed before and after dialysis therapy initiation. STUDY DESIGN: Retrospective analysis of a prospective computerized vascular access database. SETTING & PARTICIPANTS: Patients with chronic kidney disease receiving their first arteriovenous graft (n = 248) at a large medical center. PREDICTOR: Timing of graft placement (before or after initiation of dialysis therapy). OUTCOME & MEASUREMENTS: Primary graft failure, cumulative graft survival, catheter dependence, and catheter-related bacteremia. RESULTS: The first graft was placed predialysis in 62 patients and postdialysis in 186 patients. Primary graft failure was similar for pre- and postdialysis grafts (20% vs 24%; P = 0.5). Median cumulative graft survival was similar for pre- and postdialysis grafts (365 vs 414 days; HR, 1.22; 95% CI, 0.81-1.98; P = 0.3). Median duration of catheter dependence after graft placement in the postdialysis group was 48 days and was associated with 0.63 (95% CI, 0.48-0.79) episodes of catheter-related bacteremia per patient. LIMITATIONS: Retrospective analysis, single medical center. CONCLUSION: Grafts placed predialysis have primary failure rates and cumulative survival similar to those placed after starting dialysis therapy. However, postdialysis graft placement is associated with prolonged catheter dependence and frequent bacteremia. Predialysis graft placement may decrease catheter dependence and bacteremia in selected patients.

Management of complications in renal replacement therapy.

Renal replacement therapies (RRTs) are frequently employed for treatment of patients suffering from acute kidney injury in the intensive care unit (ICU). Multiple modalities of RRT are currently available. These include intermittent hemodialysis, continuous renal replacement therapies, and hybrid therapies, such as sustained low-efficiency dialysis. Because of the high complexity of ICU patients, physicians must be aware of the limitations and complications of both intermittent and continuous dialysis modalities that can contribute to patient morbidity and mortality. In this article, we highlight the recognized complications of RRTs and the treatment approach to these complications.

A physiologic-based approach to the treatment of acute hyperkalemia.

Hyperkalemia is a common and potentially lethal disorder. Given its variable presentation, clinicians should have a high index of suspicion, especially in patients with chronic kidney disease. The present case highlights key physiologic mechanisms in the development of hyperkalemia and provides an outline for emergent treatment. In this context, we discuss specific mechanisms of action of available treatments of hyperkalemia.

Phase III Trial of Intravenous Mannitol Versus Placebo During Nephron-sparing Surgery: Post Hoc Analysis of 3-yr Outcomes.

Our recently reported phase III trial demonstrated that patients undergoing nephron-sparing surgery (NSS) with an estimated glomerular filtration rate (eGFR) of ≥45 ml/min/1.73 m2 who received mannitol had no improvement in renal function at 6 mo compared with those who received placebo. Some authors have suggested that benefit is restricted to subgroups, such as those with comorbidities. We assessed whether preoperative eGFR, or other patient and surgical factors modified the effect of mannitol on postoperative outcomes at 6 mo and with extended follow-up. We also assessed whether mannitol was associated with differences in long-term GFR years after surgery. No significant difference between the mannitol or placebo groups (mean eGFR difference: 1.4; 95% confidence interval: -2.6, 5.3; p = 0.5) was found in the 134 patients with known eGFR at 3 yr after NSS. At both 6 mo and 3 yr, the effect of mannitol was not significantly modified by patient or surgical factors including preoperative eGFR. In summary, we validated our original trial conclusions by finding that intraoperative use of mannitol does not improve either short- or long-term renal function in patients undergoing NSS. Specifically, there is no evidence that comorbidities, including lower preoperative eGFR, modify the effect of mannitol. PATIENT SUMMARY: Use of mannitol at the time of partial nephrectomy does not improve either short- or long-term renal function even in patients with comorbidities, including lower preoperative renal function. The routine use of intraoperative mannitol should be discontinued.

Modulatory effects of hypercapnia on in vitro and in vivo pulmonary endothelial-neutrophil adhesive responses during inflammation.

Reducing tidal volume as a part of a protective ventilation strategy may result in hypercapnia. In this study, we focused on the influence of hypercapnia on endothelial-neutrophil responses in models of inflammatory-stimulated human pulmonary microvascular endothelial cells (HMVEC) and in an animal model of lipopolysaccharide (LPS)-induced acute lung injury. Neutrophil adhesion and adhesion molecules expression and nuclear factor-kappaB (NF-kappaB) were analyzed in TNF-alpha and LPS-treated HMVEC exposed to either eucapnia or hypercapnia. In the in vivo limb, bronchoalveolar lavage fluid cell counts and differentials, adhesion molecule and chemokine expression were assessed in LPS-treated rabbits ventilated with either low tidal volume ventilation and eucapnia or hypercapnia. In both the in vitro and in vivo models, hypercapnia significantly increased neutrophil adhesion and adhesion molecule expression compared to eucapnia. Activity of NF-kappaB was significantly enhanced by hypercapnia in the in vitro experiments. IL-8 expression was greatest both in vitro and in vivo under conditions of hypercapnia and concomitant inflammation. CD11a expression was greatest in isolated human neutrophils exposed to hypercapnia+LPS. Our results demonstrate that endothelial-neutrophil responses per measurement of fundamental molecules of adhesion are significantly increased during hypercapnia and that hypercapnia mimics conditions of eucapnia+inflammation.

Clinical and Regulatory Considerations for Central Venous Catheters for Hemodialysis.

Central venous catheters remain a vital option for access for patients receiving maintenance hemodialysis. There are many important and evolving clinical and regulatory considerations for all stakeholders for these devices. Innovation and transparent and comprehensive regulatory review of these devices is essential to stimulate innovation to help promote better outcomes for patients receiving maintenance hemodialysis. A workgroup that included representatives from academia, industry, and the US Food and Drug Administration was convened to identify the major design considerations and clinical and regulatory challenges of central venous catheters for hemodialysis. Our intent is to foster improved understanding of these devices and provide the foundation for strategies to foster innovation of these devices.

RIPK3 promotes kidney fibrosis via AKT-dependent ATP citrate lyase.

Renal fibrosis is a common pathogenic response to injury in chronic kidney disease (CKD). The receptor-interacting protein kinase-3 (RIPK3), a regulator of necroptosis, has been implicated in disease pathogenesis. In mice subjected to unilateral ureteral obstruction-induced (UUO-induced) or adenine diet-induced (AD-induced) renal fibrosis, models of progressive kidney fibrosis, we demonstrate increased kidney expression of RIPK3. Mice genetically deficient in RIPK3 displayed decreased kidney fibrosis and improved kidney function relative to WT mice when challenged with UUO or AD. In contrast, mice genetically deficient in mixed-lineage kinase domain-like protein (MLKL), a downstream RIPK3 target, were not protected from UUO-induced kidney fibrosis. We demonstrate a pathway by which RIPK3 promotes fibrogenesis through the AKT-dependent activation of ATP citrate lyase (ACL). Genetic or chemical inhibition of RIPK3 suppressed the phosphorylation of AKT and ACL in response to TGF-ß1 in fibroblasts. Inhibition of AKT or ACL suppressed TGF-ß1-dependent extracellular matrix production and myofibroblast differentiation in fibroblasts. Pharmacological inhibition of ACL suppressed UUO-induced kidney fibrosis. RIPK3 expression was highly regulated in human CKD kidney. In conclusion, we identify a pathway by which RIPK3 promotes kidney fibrosis independently of MLKL-dependent necroptosis as a promising therapeutic target in CKD.

Benign and tumor parenchyma metabolomic profiles affect compensatory renal growth in renal cell carcinoma surgical patients.

BACKGROUND AND OBJECTIVES: Pre-operative kidney volume is an independent predictor of glomerular filtration rate in renal cell carcinoma patients. Compensatory renal growth (CRG) can ensue prior to nephrectomy in parallel to tumor growth and benign parenchyma loss. We aimed to test whether renal metabolite abundances significantly associate with CRG, suggesting a causative relationship. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Tissue metabolomics data from 49 patients, with a median age of 60 years, were previously collected and the pre-operative fold-change of their contra to ipsi-lateral benign kidney volume served as a surrogate for their CRG. Contra-lateral kidney volume fold-change within a 3.3 +/- 2.1 years follow-up interval was used as a surrogate for long-term CRG. Using a multivariable statistical model, we identified metabolites whose abundances significantly associate with CRG. RESULTS: Our analysis found 13 metabolites in the benign (e.g. L-urobilin, Variable Influence in Projection, VIP, score = 3.02, adjusted p = 0.017) and 163 metabolites in the malignant (e.g. 3-indoxyl-sulfate, VIP score = 1.3, adjusted p = 0.044) tissues that significantly associate with CRG. Benign/tumor fold change in metabolite abundances revealed three additional metabolites with that significantly positively associate with CRG (e.g. p-cresol sulfate, VIP score = 2.945, adjusted p = 0.033). At the pathway level, we show that fatty-acid oxidation is highly enriched with metabolites whose benign tissue abundances strongly positively associate with CRG, both pre-operatively and long term, whereas in the tumor tissue significant enrichment of dipeptides and benzoate (positive association), glycolysis/gluconeogenesis, lysolipid and nucleotide sugar pentose (negative associations) sub-pathways, were observed. CONCLUSION: These data suggest that specific biological processes in the benign as well as in the tumor parenchyma strongly influence compensatory renal growth.