Immunogenicity of SARS-CoV-2 Vaccine in Dialysis.

BACKGROUND: Patients receiving maintenance dialysis represent a high-risk, immune-compromised population with 15%-25% COVID-19 mortality rate who were unrepresented in clinical trials of mRNA vaccines. METHODS: All patients receiving maintenance dialysis who received two doses of SARS-CoV-2 mRNA vaccines with antibody test results drawn ≥14 days after the second dose, as documented in the electronic health record through March 18, 2021, were included. Response was on the basis of levels of Ig-G against the receptor binding domain of the S1 subunit of SARS-CoV-2 spike-antigen (seropositive ≥2 U/L) using an FDA-approved semiquantitative chemiluminescent assay (ADVIA Centaur XP/XPT COV2G). RESULTS: Among 186 patients on dialysis from 30 clinics in eight states tested 23±8 days after receiving two vaccine doses, there were 165 (88.7%) responders with 70% at maximum titer. There was no significant difference between BNT162b2/Pfizer (148 out of 168, 88.1%) and mRNA-1273/Moderna (17 out of 18, 94.4%), P=0.42. All 38 patients with COVID-19 history were responders, with 97% at maximum titer. Among patients without COVID-19, 127 out of 148 (85.8%) were responders, comparable between BNT162b2/Pfizer (113 out of 133) and mRNA-1273/Moderna (14 out of 15) vaccines (85.0% versus 93.3%, P=0.38). CONCLUSIONS: Most patients receiving maintenance dialysis responded after two doses of BNT162b2/Pfizer or mRNA-1273/Moderna vaccine, suggesting the short-term development of antispike antibody is good, giving hope that most of these patients who are vulnerable, once immunized, will be protected from COVID-19. Longer-term evaluation is needed to determine antibody titer durability and if booster dose(s) are warranted. Further research to evaluate the approach to patients without a serologic response is needed, including benefits of additional dose(s) or administration of alternate options.

Transcriptomics of Human Arteriovenous Fistula Failure: Genes Associated With Nonmaturation.

RATIONALE & OBJECTIVE: Improving arteriovenous fistula (AVF) outcomes requires better understanding of the biology underlying maturation or failure. Our current knowledge of maturation relies on extrapolation from other vascular pathologies, which does not incorporate unique aspects of AVF remodeling. This study compares the RNA expression of pre-access (native) veins and AVFs with distinct maturation outcomes. STUDY DESIGN: Case-control study. SETTING & PARTICIPANTS: 64 patients undergoing 2-stage AVF surgeries at a single center. 19 native veins and 19 AVF samples were analyzed using RNA sequencing (RNA-seq). 58 native veins were studied using real-time polymerase chain reaction; 45, using immunohistochemistry; and 19, using Western blot analysis. PREDICTOR: RNA expression in native veins and AVFs. OUTCOME: Anatomic nonmaturation, defined as an AVF that never achieved an internal diameter ≥ 6mm. ANALYTICAL APPROACH: Pre-access native veins and AVF samples were obtained from patients undergoing 2-stage AVF creation. Veins that subsequently matured or failed after access creation were analyzed using RNA-seq to search for genes associated with maturation failure. Genes associated with nonmaturation were confirmed using real-time polymerase chain reaction, immunohistochemistry, and Western blot analysis. In addition, the association between pre-access gene expression and postoperative morphology was evaluated. RNA-seq was also performed on AVFs to search for transcriptional differences between AVFs that matured and those that failed at the time of transposition. RESULTS: Pro-inflammatory genes (CSF3R, FPR1, S100A8, S100A9, and VNN2) were upregulated in pre-access veins that failed (false discovery rate < 0.05), and their expression colocalized to smooth muscle cells. Expression of S100A8 and S100A9 correlated with postoperative intimal hyperplasia and the product of medial fibrosis and intimal hyperplasia (r=0.32-0.38; P < 0.05). AVFs that matured or failed were transcriptionally similar at the time of transposition. LIMITATIONS: Small sample size, analysis of only upper-arm veins and transposed fistulas. CONCLUSIONS: Increased expression of proinflammatory genes in pre-access veins appears to be associated with greater risk for AVF nonmaturation.

Fibrotic Venous Remodeling and Nonmaturation of Arteriovenous Fistulas.

The frequency of primary failure in arteriovenous fistulas (AVFs) remains unacceptably high. This lack of improvement is due in part to a poor understanding of the pathobiology underlying AVF nonmaturation. This observational study quantified the progression of three vascular features, medial fibrosis, intimal hyperplasia (IH), and collagen fiber organization, during early AVF remodeling and evaluated the associations thereof with AVF nonmaturation. We obtained venous samples from patients undergoing two-stage upper-arm AVF surgeries at a single center, including intraoperative veins at the first-stage access creation surgery and AVFs at the second-stage transposition procedure. Paired venous samples from both stages were used to evaluate change in these vascular features after anastomosis. Anatomic nonmaturation (AVF diameter never ≥6 mm) occurred in 39 of 161 (24%) patients. Neither preexisting fibrosis nor IH predicted AVF outcomes. Postoperative medial fibrosis associated with nonmaturation (odds ratio [OR], 1.55; 95% confidence interval [95% CI], 1.05 to 2.30; P=0.03, per 10% absolute increase in fibrosis), whereas postoperative IH only associated with failure in those individuals with medial fibrosis over the population's median value (OR, 2.63; 95% CI, 1.07 to 6.46; P=0.04, per increase of 1 in the intima/media ratio). Analysis of postoperative medial collagen organization revealed that circumferential alignment of fibers around the lumen associated with AVF nonmaturation (OR, 1.38; 95% CI, 1.03 to 1.84; P=0.03, per 10° increase in angle). This study demonstrates that excessive fibrotic remodeling of the vein after AVF creation is an important risk factor for nonmaturation and that high medial fibrosis determines the stenotic potential of IH.

Dialysis Arteriovenous Fistula Failure and Angioplasty: Intimal Hyperplasia and Other Causes of Access Failure.

The arteriovenous fistula (AVF) is the preferred hemodialysis access type because it has better patency rates and fewer complications than other access types. However, primary failure remains a common problem impeding AVF maturation and adding to patients' morbidity and mortality. Juxta-anastomotic (or inflow) stenosis is the most common reason leading to primary failure, and percutaneous transluminal angioplasty continues to be the gold-standard treatment with excellent success rates. Intimal hyperplasia (IH) has been traditionally blamed as the main pathophysiologic culprit, but new evidence raises doubts regarding the contribution of IH alone to primary failure. We report a 64-year-old man with a 2-stage brachiobasilic AVF that was complicated by failure 4 months after creation. An angiogram showed multiple juxta-anastomotic and midfistula stenotic lesions. Percutaneous transluminal angioplasty was successful in assisting maturation and subsequently cannulating the AVF for hemodialysis treatment. We failed to identify the underlying cause of stenosis because biopsy specimens from fistula tissue obtained at the time of transposition revealed no occlusive IH. This case emphasizes the need for additional research on factors contributing to AVF failure besides IH and highlights the need for more therapeutic options to reduce AVF failure rate.

Pre-existing and Postoperative Intimal Hyperplasia and Arteriovenous Fistula Outcomes.

BACKGROUND: The contribution of intimal hyperplasia (IH) to arteriovenous fistula (AVF) failure is uncertain. This observational study assessed the relationship between pre-existing, postoperative, and change in IH over time and AVF outcomes. STUDY DESIGN: Prospective cohort study with longitudinal assessment of IH at the time of AVF creation (pre-existing) and transposition (postoperative). Patients were followed up for up to 3.3 years. SETTING & PARTICIPANTS: 96 patients from a single center who underwent AVF surgery initially planned as a 2-stage procedure. Veins and AVF samples were collected from 66 and 86 patients, respectively. Matched-pair tissues were available from 56 of these patients. PREDICTORS: Pre-existing, postoperative, and change in IH over time. OUTCOMES: Anatomic maturation failure was defined as an AVF that never reached a diameter > 6mm. Primary unassisted patency was defined as the time elapsed from the second-stage surgery to the first intervention. MEASUREMENTS: Maximal intimal thickness in veins and AVFs and change in intimal thickness over time. RESULTS: Pre-existing IH (>0.05mm) was present in 98% of patients. In this group, the median intimal thickness increased 4.40-fold (IQR, 2.17- to 4.94-fold) between AVF creation and transposition. However, this change was not associated with pre-existing thickness (r(2)=0.002; P=0.7). Ten of 96 (10%) AVFs never achieved maturation, whereas 70% of vascular accesses remained patent at the end of the observational period. Postoperative IH was not associated with anatomic maturation failure using univariate logistic regression. Pre-existing, postoperative, and change in IH over time had no effects on primary unassisted patency. LIMITATIONS: The small number of patients from whom longitudinal tissue samples were available and low incidence of anatomic maturation failure, which decreased the statistical power to find associations between end points and IH. CONCLUSIONS: Pre-existing, postoperative, and change in IH over time were not associated with 2-stage AVF outcomes.

The impact of arteriovenous fistulae on the myocardium: the impact of creation and ligation in the transplant era.

Cardiac hypertrophy is a relatively common complication seen in patients with advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD). Moreover, cardiac hypertrophy is even more frequently seen in patients with ESRD who have an arteriovenous (AV) access. There has been substantial evidence pertaining to the effects of AV access creation on the heart structure and function. Similarly, there is increasing evidence on the effects of AV access closure, flow reduction, transplantation, and immunosuppressive medication on both endpoints. In this review, we present the evidence available in the literature on these topics and open the dialog for further research in this interesting field.

c-Kit signaling determines neointimal hyperplasia in arteriovenous fistulae.

Stenosis of arteriovenous (A-V) fistulae secondary to neointimal hyperplasia (NIH) compromises dialysis delivery, which worsens patients' quality of life and increases medical costs associated with the maintenance of vascular accesses. In the present study, we evaluated the role of the receptor tyrosine kinase c-Kit in A-V fistula neointima formation. Initially, c-Kit was found in the neointima and adventitia of human brachiobasilic fistulae, whereas it was barely detectable in control veins harvested at the time of access creation. Using the rat A-V fistula model to study venous vascular remodeling, we analyzed the spatial and temporal pattern of c-Kit expression in the fistula wall. Interestingly, c-Kit immunoreactivity increased with time after anastomosis, which concurred with the accumulation of cells in the venous intima. In addition, c-Kit expression in A-V fistulae was positively altered by chronic kidney failure conditions. Both blockade of c-Kit with imatinib mesylate (Gleevec) and inhibition of stem cell factor production with a specific short hairpin RNA prevented NIH in the outflow vein of experimental fistulae. In agreement with these data, impaired c-Kit activity compromised the development of NIH in A-V fistulae created in c-KitW/Wv mutant mice. These results suggest that targeting of the c-Kit signaling pathway may be an effective approach to prevent postoperative NIH in A-V fistulae.

Single-Cell Analyses Offer Insights into the Different Remodeling Programs of Arteries and Veins.

Arteries and veins develop different types of occlusive diseases and respond differently to injury. The biological reasons for this discrepancy are not well understood, which is a limiting factor for the development of vein-targeted therapies. This study contrasts human peripheral arteries and veins at the single-cell level, with a focus on cell populations with remodeling potential. Upper arm arteries (brachial) and veins (basilic/cephalic) from 30 organ donors were compared using a combination of bulk and single-cell RNA sequencing, proteomics, flow cytometry, and histology. The cellular atlases of six arteries and veins demonstrated a 7.8× higher proportion of contractile smooth muscle cells (SMCs) in arteries and a trend toward more modulated SMCs. In contrast, veins showed a higher abundance of endothelial cells, pericytes, and macrophages, as well as an increasing trend in fibroblasts. Activated fibroblasts had similar proportions in both types of vessels but with significant differences in gene expression. Modulated SMCs and activated fibroblasts were characterized by the upregulation of MYH10, FN1, COL8A1, and ITGA10. Activated fibroblasts also expressed F2R, POSTN, and COMP and were confirmed by F2R/CD90 flow cytometry. Activated fibroblasts from veins were the top producers of collagens among all fibroblast populations from both types of vessels. Venous fibroblasts were also highly angiogenic, proinflammatory, and hyper-responders to reactive oxygen species. Differences in wall structure further explain the significant contribution of fibroblast populations to remodeling in veins. Fibroblasts are almost exclusively located outside the external elastic lamina in arteries, while widely distributed throughout the venous wall. In line with the above, ECM-targeted proteomics confirmed a higher abundance of fibrillar collagens in veins vs. more basement ECM components in arteries. The distinct cellular compositions and transcriptional programs of reparative populations in arteries and veins may explain differences in acute and chronic wall remodeling between vessels. This information may be relevant for the development of antistenotic therapies.

The anatomical sources of neointimal cells in the arteriovenous fistula.

Neointimal cells are an elusive population with ambiguous origins, functions, and states of differentiation. Expansion of the venous intima in arteriovenous fistula (AVF) is one of the most prominent remodeling processes in the wall after access creation. However, most of the current knowledge about neointimal cells in AVFs comes from extrapolations from the arterial neointima in non-AVF systems. Understanding the origin of neointimal cells in fistulas may have important implications for the design and effective delivery of therapies aimed to decrease intimal hyperplasia (IH). In addition, a broader knowledge of cellular dynamics during postoperative remodeling of the AVF may help clarify other transformation processes in the wall that combined with IH determine the successful remodeling or failure of the access. In this review, we discuss the possible anatomical sources of neointimal cells in AVFs and their relative contribution to intimal expansion.

Functions for platelet factor 4 (PF4/CXCL4) and its receptors in fibroblast-myofibroblast transition and fibrotic failure of arteriovenous fistulas (AVFs).

BACKGROUND: Over 60% of End Stage Renal Disease (ESRD) patients are relying on hemodialysis (HD) to survive, and the arteriovenous fistula (AVF) is the preferred vascular access method for HD. However approximately half of all newly created AVF fail to mature and cannot be used without a salvage procedure. We have recently demonstrated an association between AVF maturation failure and post-operative fibrosis, while our RNA-seq study also revealed that veins that ultimately failed during AVF maturation had elevated levels of platelet factor 4 (PF4/CXCL4). However, a link between these two findings was yet to be established. METHODS: In this study, we investigated potential mechanisms between PF4 levels and fibrotic remodeling in veins. We compared the local expression of PF4 and fibrosis marker integrin ß6 (ITGB6) in veins that successfully underwent maturation with that in veins that ultimately failed to mature. We also measured the changes of expression level of α-smooth muscle actin (αSMA/ACTA2) and collagen (Col1/COL1A1) in venous fibroblasts upon various treatments, such as PF4 pharmacological treatment, alteration of PF4 expression, and blocking of PF4 receptors. RESULTS: We found that PF4 is expressed in veins and co-localizes with αSMA. In venous fibroblasts, PF4 stimulates expression of αSMA and Col1 via different pathways. The former requires integrins αvß5 and α5ß1, while chemokine receptor CXCR3 is needed for the latter. Interestingly, we also discovered that the expression of PF4 is associated with that of ITGB6, the ß subunit of integrin αvß6. This integrin is critical for the activation of the major fibrosis factor TGFß, and overexpression of PF4 promotes activation of the TGFß pathway. CONCLUSIONS: These results indicate that upregulation of PF4 may cause venous fibrosis both directly by stimulating fibroblast differentiation and expression of extracellular matrix (ECM) molecules and indirectly by facilitating the activation of the TGFß pathway.

The Transcriptomics of the Human Vein Transformation After Arteriovenous Fistula Anastomosis Uncovers Layer-Specific Remodeling and Hallmarks of Maturation Failure.

Introduction: The molecular transformation of the human preaccess vein after arteriovenous fistula (AVF) creation is poorly understood. This limits our ability to design efficacious therapies to improve maturation outcomes. Methods: Bulk RNA sequencing (RNA-seq) followed by paired bioinformatic analyses and validation assays were performed in 76 longitudinal vascular biopsies (veins and AVFs) from 38 patients with stage 5 chronic kidney disease or end-stage kidney disease undergoing surgeries for 2-stage AVF creation (19 matured, 19 failed). Results: A total of 3637 transcripts were differentially expressed between veins and AVFs independent of maturation outcomes, with 80% upregulated in fistulas. The postoperative transcriptome demonstrated transcriptional activation of basement membrane and interstitial extracellular matrix (ECM) components, including preexisting and novel collagens, proteoglycans, hemostasis factors, and angiogenesis regulators. A postoperative intramural cytokine storm involved >80 chemokines, interleukins, and growth factors. Postoperative changes in ECM expression were differentially distributed in the AVF wall, with proteoglycans and fibrillar collagens predominantly found in the intima and media, respectively. Interestingly, upregulated matrisome genes were enough to make a crude separation of AVFs that failed from those with successful maturation. We identified 102 differentially expressed genes (DEGs) in association with AVF maturation failure, including upregulation of network collagen VIII in medial smooth muscle cells (SMCs) and downregulation of endothelial-predominant transcripts and ECM regulators. Conclusion: This work delineates the molecular changes that characterize venous remodeling after AVF creation and those relevant to maturation failure. We provide an essential framework to streamline translational models and our search for antistenotic therapies.

A new arteriovenous fistula model to study the development of neointimal hyperplasia.

This study describes an alternative arteriovenous fistula (AVF) model in the rat in which the animals develop significant neointimal hyperplasia (NIH) not only at the distal anastomotic site, but also throughout the fistula body. This aortocaval fistula was established by anastomosing the distal end of the renal vein to the abdominal aorta after unilateral nephrectomy. The increased hemodynamic stress resulting from exposing the renal vein to the arterial circulation induced venous NIH as early as 7 days after surgery. This experimental AVF was characterized by the early lack of endothelium, the accumulation of proliferating vascular smooth muscle cells and the neovascularization of the fistula adventitia. In summary, we have described an informative animal model to study the pathobiology of NIH in native AVF.

Clinical Aspects of Dialysis Interventions: Physical and Sonographic Findings.

Physical examination (PE) of arteriovenous access remains of high clinical value and continues to be recommended by leading societies and guidelines. PE is easy to learn and perform. Once learned, examiners can provide a comprehensive arteriovenous (AV) access examination in 20 to 30 seconds. Therefore, we continue to advocate that AV access PE should be part of the training for all dialysis care providers. Similarly, ultrasound can provide important AV access evaluation and provide key information. It is relatively cheap and can be readily available at the bed side. Additionally, it is well accepted by patients, as it is not expected to be associated with pain or discomfort during the examination. We present in this review the key components of PE, signs and symptoms of AV access dysfunction, and the role of ultrasound in AV access evaluation as a complementary tool to PE.

Role of platelet factor 4 in arteriovenous fistula maturation failure: What do we know so far?

The rate of arteriovenous fistula (AVF) maturation failure remains unacceptably high despite continuous efforts on technique improvement and careful pre-surgery planning. In fact, half of all newly created AVFs are unable to be used for hemodialysis (HD) without a salvage procedure. While vascular stenosis in the venous limb of the access is the culprit, the underlying factors leading to vascular narrowing and AVF maturation failure are yet to be determined. We have recently demonstrated that AVF non-maturation is associated with post-operative medial fibrosis and fibrotic stenosis, and post-operative intimal hyperplasia (IH) exacerbates the situation. Multiple pathological processes and signaling pathways are underlying the stenotic remodeling of the AVF. Our group has recently indicated that a pro-inflammatory cytokine platelet factor 4 (PF4/CXCL4) is upregulated in veins that fail to mature after AVF creation. Platelet factor 4 is a fibrosis marker and can be detected in vascular stenosis tissue, suggesting that it may contribute to AVF maturation failure through stimulation of fibrosis and development of fibrotic stenosis. Here, we present an overview of the how PF4-mediated fibrosis determines AVF maturation failure.

Systemic Profile of Cytokines in Arteriovenous Fistula Patients and Their Associations with Maturation Failure.

Background: Systemic cytokines are elevated in patients with chronic kidney disease (CKD) and on hemodialysis compared with the general population. However, whether cytokine levels interfere with vascular remodeling, increasing the risk of arteriovenous fistula (AVF) failure, remains unknown. Methods: This is a case-control study of 64 patients who underwent surgery for AVF creation (32 with AVF maturation failure and 32 matching controls with successful maturation). A total of 74 cytokines, including chemokines, interferons, interleukins, and growth factors, were measured in preoperative plasma samples using multiplex assays. Sixty-two patients were included in the statistical analyses. Associations with AVF failure were assessed using paired comparisons and conditional logistic regressions accounting for paired strata. Results: Seven cytokines were significantly higher in patients with AVF maturation failure than in matching controls (G-CSF, IL-6, MDC, RANTES, SDF-1α/ß, TGFα, and TPO). Of these, G-CSF (odds ratio [OR]=1.71; 95% confidence interval [95% CI], 1.05 to 2.79 per 10 pg/ml), MDC (OR=1.60, 95% CI, 1.08 to 2.38 per 100 pg/ml), RANTES (OR=1.55, 95% CI, 1.10 to 2.17 per 100 pg/ml), SDF-1α/ß (OR=1.18, 95% CI, 1.04 to 1.33 per 1000 pg/ml), and TGFα (OR=1.39, 95% CI 1.003, 1.92 per 1 pg/ml) showed an incremental association by logistic regression. Conclusions: This study identified a profile of plasma cytokines associated with adverse maturation outcomes in AVFs. These findings may open the doors for future therapeutics and markers for risk stratification.

Vein morphometry in end-stage kidney disease: Teasing out the contribution of age, comorbidities, and vintage to chronic wall remodeling.

Background: Chronic kidney disease (CKD) is a highly comorbid condition with significant effects on vascular health and remodeling. Upper extremity veins are important in end-stage kidney disease (ESKD) due to their potential use to create vascular accesses. However, unlike arteries, the contribution of CKD-associated factors to the chronic remodeling of veins has been barely studied. Methods: We measured morphometric parameters in 315 upper extremity veins, 131 (85% basilic) from stage 5 CKD/ESKD patients and 184 (89% basilic) from non-CKD organ donors. Associations of demographic and clinical characteristics with intimal hyperplasia (IH) and medial fibrosis were evaluated using multivariate regression models. Results: The study cohort included 33% females, 30% blacks, 32% Hispanics, and 37% whites. Over 60% had hypertension, and 25% had diabetes independent of CKD status. Among kidney disease participants, 26% had stage 5 CKD, while 22 and 52% had ESKD with and without history of a previous arteriovenous fistula/graft (AVF/AVG), respectively. Intimal hyperplasia was associated with older age (ß = 0.13 per year, confidence interval [CI] = 0.002-0.26), dialysis vintage > 12 months (ß = 0.22, CI = 0.09-0.35), and previous AVF/AVG creation (ß = 0.19, CI = 0.06-0.32). Upper quartile values of IH were significantly associated with diabetes (odds ratio [OR] = 2.02, CI = 1.08-3.80), which demonstrated an additive effect with previous AVF/AVG history and longer vintage in exacerbating IH. Medial fibrosis also increased as a function of age (ß = 0.17, CI = 0.04-0.30) and among patients with diabetes (ß = 0.15, CI = 0.03-0.28). Age was the predominant factor predicting upper quartile values of fibrosis (OR = 1.03 per year, CI = 1.01-1.05) independent of other comorbidities. Conclusion: Age and diabetes are the most important risk factors for chronic development of venous IH and fibrosis independent of CKD status. Among kidney disease patients, longer dialysis vintage, and history of a previous AVF/AVG are strong predictors of IH.

Origin of neointimal cells in arteriovenous fistulae: bone marrow, artery, or the vein itself?

To elucidate the source of neointimal cells, experimental fistulas were created in Lewis wild-type (WT) and transgenic rats that constitutively expressed the green fluorescent protein (GFP) in all tissues. Arteriovenous fistula (AVFs) were created by anastomosing the left renal vein to the abdominal aorta. The contribution of bone marrow (BM)-derived cells to the AVF neointima was examined in lethally irradiated WT rats that had been rescued with GFP BM cells. Neointimal cells in these chimeric rats were mostly GFP negative indicating the non-BM origin of those cells. Then, the contribution of arterial cells to the AVF neointima was assessed in a fistula made with a GFP aorta that had been implanted orthotopically into a WT rat. Most of the neointimal cells were also GFP negative demonstrating that AVF neointimal cells are not derived from the feeding artery. Finally to study local resident cells contribution to the formation of neointimal lesions, a composite fistula was created by interposing a GFP vein between the renal vein and the aorta in a WT recipient rat. GFP neointimal cells were only found in the transplanted vein. This study suggests that neointimal cells originate from the local resident cells in the venous limb of the fistula.

Intimal Hyperplasia and Arteriovenous Fistula Failure: Looking Beyond Size Differences.

The development of venous intimal hyperplasia (IH) has been historically associated with failure of arteriovenous fistulas (AVF) used for hemodialysis. This long-standing assumption, based on histological observations, has been recently challenged by clinical studies indicating that the size of the intima by itself is not enough to explain stenosis or AVF maturation failure. Irrespective of this lack of association, IH is present in most native veins and fistulas, is prominent in many cases, and suggests a role in the vein that may not be reflected by its dimensions. Therefore, the contribution of IH to AVF dysfunction remains controversial. Using only clinical data and avoiding extrapolations from animal models, we critically discuss the biological significance of IH in vein remodeling, vascular access function, and the response of the venous wall to repeated trauma in hemodialysis patients. We address questions and pose new ones such as: What are the factors that contribute to IH in pre-access veins and AVFs? Do cellular phenotypes and composition of the intima influence AVF function? Are there protective roles of the venous intima? This review explores these possibilities, with hopes of rekindling a critical discussion about venous IH that goes beyond thickness and AVF outcomes.

A hyaluronan synthesis inhibitor delays the progression of diabetic kidney disease in a mouse experimental model.

BACKGROUND: The role of hyaluronan (HA) in the development and progression of diabetic kidney disease (DKD), as well as the precise mechanisms and consequences of HA involvement in this pathology are still to be clarified. METHODS: In this study, we assayed the effects of the HA synthesis inhibitor 4-methylumbelliferone (4-MU) on the development of DKD. Diabetic type 2 model mice (eNOS-/- C57BLKS/Jdb) were fed artificial diets containing 5% 4-MU or not for 9 weeks. Plasma glucose, glomerular filtration rate (GFR), albumin to creatinine ratio (ACR), and biomarkers of kidney function and systemic inflammation were measured at baseline and after treatment. Diabetic nephropathy was further characterized in treated and control mice by histopathology. RESULTS: Treated animals consumed a daily dose of approximately 6.2 g of 4-MU per kg of body weight. At the end of the experimental period, the 4-MU supplemented diet resulted in a significant decrease in non-fasting plasma glucose (516 [interquartile range 378-1170] vs. 1149 [875.8-1287] mg/dL, P=0.050) and a trend toward lower HA kidney content (5.6 ± 1.5 vs. 8.8 ± 3.1 ng/mg of kidney weight, P=0.070) compared to the control diet, respectively. Diabetic animals treated with 4-MU showed significantly higher GFR and lower urine ACR and plasma cystatin C levels than diabetic controls. Independent histological assessment of DKD also demonstrated a significant decrease in mesangial expansion score and glomerular injury index in 4-MU-treated mice compared to controls. Plasma glucose showed a strong correlation with kidney HA levels (r=0.66, P=0.0098). Both total hyaluronan (r=0.76, P=0.0071) and low-molecular-weight hyaluronan content (r=0.64, P=0.036) in the kidneys correlated with urine ACR in mice. CONCLUSION: These results show that the hyaluronan synthesis inhibitor 4-MU effectively slowed the progression of DKD and constitutes a potential new therapeutic approach to treat DKD.

Effect of intensive blood pressure on the progression of non-diabetic chronic kidney disease at varying degrees of proteinuria.

The ideal blood pressure (BP) target for renoprotection is uncertain in patients with non-diabetic chronic kidney disease (CKD), especially considering the influence exerted by pre-existing proteinuria. In this pooled analysis of landmark trials, we coalesced individual data from 5001 such subjects randomized to intensive versus standard BP targets. We employed multivariable regression to evaluate the relationship between follow-up systolic blood pressure (SBP) and diastolic blood pressure (DBP) on CKD progression (defined as glomerular filtration rate decline by 50% or end-stage renal disease), focusing on the potential for effect modification by baseline proteinuria or albuminuria. The median follow-up was 3.2 years. We found that SBP rather than DBP was the primary predictor of renal outcomes. The optimal SBP target was 110-129 mm Hg. We observed a strong interaction between SBP and proteinuria such that lower SBP ranges were significantly linked with progressively lower CKD risk in grade A3 albuminuria or ≥0.5-1 g/day proteinuria (relative to SBP 110-119 mm Hg, the adjusted HR for SBP 120-129 mm Hg, 130-139 mm Hg, and 140-149 mm Hg was 1.5, 2.3, and 3.3, respectively; all p<0.05). In grade A2 microalbuminuria or proteinuria near 0.5 g/day, a non-significant but possible connection was seen between tighter BP and decreased CKD (aforementioned HRs all <2; all p>0.05), while in grade A1 albuminuria or proteinuria <0.2 g/day no significant association was apparent (HRs all <1.5; all p>0.1). We conclude that in non-diabetic CKD, stricter BP targets <130 mm Hg may help limit CKD progression as proteinuria rises.