Inactive Matrix Gla Protein, Arterial Stiffness, and Endothelial Function in African American Hemodialysis Patients.

BACKGROUND: Matrix Gla protein (MGP) is a vascular calcification inhibitor dependent upon vitamin K for activation. Evidence suggests that elevated plasma inactive MGP levels (desphospho-uncarboxylated MGP, dp-ucMGP; indicating poorer vascular vitamin K status) are associated with greater cardiovascular disease (CVD) risk. Despite African Americans experiencing highest rates of kidney failure and CVD events, relationships between dp-ucMGP and CVD risk markers have not been examined in this population. We investigated vascular vitamin K status (via plasma dp-ucMGP) between African American hemodialysis (HD) patients and healthy controls, and the associations of dp-ucMGP with arterial stiffness and endothelial function in HD patients only. METHODS: In 37 African American HD patients and 37 age- and race-matched controls, plasma dp-ucMGP was measured by enzyme immunoassay as a marker of vascular vitamin K status. Carotid-femoral pulse wave velocity (PWV; arterial stiffness measurement) and brachial artery flow-mediated dilation (FMD; endothelial function measurement) were assessed by applanation tonometry and ultrasound, respectively, in HD patients only. RESULTS: Mean dp-ucMGP levels were 5.6 times higher in HD patients vs. controls (2,139 ± 1,102 vs. 382 ± 181 pmol/l, P < 0.01). Multiple linear regression, adjusting for age, sex, dialysis vintage, diabetes mellitus, CVD history, body mass index, and blood pressure, revealed that dp-ucMGP was independently related to PWV (standardized ß = 0.49) and FMD (standardized ß = -0.53) (both P < 0.01). CONCLUSIONS: Our data suggest that the higher plasma dp-ucMGP concentrations found in African American HD patients may be associated with greater arterial stiffness and endothelial dysfunction.

Applicability of an entry flow model of the brachial artery for flow models of the hemodialysis fistula.

The native arteriovenous fistula creates a shunt that provides the high blood flow that is needed for dialysis. Lumped parameter hemodynamic models of the arteriovenous fistula can be used to predict shear stresses and pressure losses and can be applied to help understand unsolved problems such as the high rate of arteriovenous fistula maturation failure. These models combine together flow components, such as arteries, stenosis, anastomoses, arterial compliance, and blood inertia, and each component must be modeled with an appropriate pressure-flow relationship. Poiseuille flow is generally assumed for straight vessels, but the unique high flow rates within the brachial artery of an arteriovenous fistula are expected to induce entry flow effects that are neglected in this model. To estimate the importance of these effects, brachial artery flow was modeled in a low-resistance network, such as the one that occurs when an arteriovenous fistula is constructed, through the lumped parameter model, and the predicted flow rates and pressures were compared to those predicted by computational fluid dynamics. When Poiseuille flow was assumed, the flow rate from the lumped parameter model was consistently larger than that from computational fluid dynamics, with a cycle-averaged error of 36.8%. When an entry flow model (Shah) was assumed, the lumped parameter-based flow was 6% lower than the computational fluid dynamics model at the peak of the flow waveform, and the cycle-averaged error was reduced to 7.8%. Thus, in a low-resistance (high flow) arteriovenous fistula circuit, an entry flow model can account for steeper near-wall velocity gradients. This result can provide a useful guide for designing engineering models of the arteriovenous fistula.

Volume blood flow, static pressure ratio and venous conductance in native arterio-venous fistulae: three surveillance methods compared.

PURPOSE: Dialysis venous pressure monitoring has been widely recommended as a surveillance method but has not been shown to improve access outcomes in randomised controlled trials. The method has been impaired by the need to either turn off the blood pump or to derive the static venous pressure from the venous pressure measured with the dialysis pump running. We have developed a unique algorithm which converts Doppler-shifted spectral information derived from unscaled pulsatile blood flow waveforms into an estimate of mean blood pressure (MBP) at the point of ultrasound insonation. METHODS: We have devised the unique expression shown here: MBP = MAP/(1 + Pff/Vff) where MAP is the mean arterial pressure, Pff = (systolic - diastolic)/MAP measured on the contralateral arm and Vff = spectral maximum - minimum/mean. Venous conductance (VC) can be measured by combining this pressure data with Duplex ultrasound blood flow data. A new device BlueDop™ has been used to illustrate the potential clinical value of non-invasive static pressure ratio (SPRn) in a monitoring role. Duplex and BlueDop™ technology were tested in an arterio-venous fistula (AVF) study in which VC, Q and SPRn were compared. Thresholds used for detection of ≥60% venous stenosis were VC <10 mL min-1 mm Hg-1, Q <500 mL min-1, SPRn >0.56. RESULTS: The following accuracy was achieved: VC = 96%, Q = 92%, SPRn = 76% with similar accuracy in predicting premature thrombosis. CONCLUSIONS: A new algorithm has been described and its in vivo accuracy in estimating mean 'pressure from flow' has been confirmed. Two new variables and a new dedicated instrument BlueDop™ have been demonstrated in clinical use.

Vascular access surveillance: case study of a false paradigm.

The hemodialysis vascular access surveillance controversy provides a case study of how enthusiasm for a new test or treatment can lead to adoption of a false paradigm. Paradigms are the beliefs and assumptions shared by those in a field of knowledge, and are commonly included in clinical practice guidelines. The guidelines of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative recommend that arteriovenous vascular accesses undergo routine surveillance for detection and correction of stenosis. This recommendation is based on the paradigm that surveillance of access blood flow or dialysis venous pressure combined with correction of stenosis improves access outcomes. However, the quality of evidence that supports this paradigm has been widely criticized. We tested the validity of the surveillance paradigm by applying World Health Organization (WHO) criteria for evaluating screening tests to a literature review of published vascular access studies. These criteria include four components: undesired condition, screening test, intervention, and desired outcome. The WHO criteria show that surveillance as currently practiced fails all four components and provides little or no significant benefit, suggesting that surveillance is a false paradigm. Once a paradigm is established, however, challenges to its validity are usually resisted even as new evidence indicates the paradigm is not valid. Thus, it is paramount to apply rigorous criteria when developing guidelines. Regulators may help promote needed changes in paradigms when cost and safety considerations coincide.

Differential regulation of nitric oxide synthase function in aorta and tail artery from 5/6 nephrectomized rats.

Chronic renal failure (CRF) is associated with hypertension and concomitant endothelial dysfunction, enhanced vasoconstriction, and nitric oxide synthase (NOS) dysfunction. Vascular function in patients is assessed in peripheral extremity arteries like the finger arteries, whereas animal studies often use the centrally located aorta. Therefore, we examined whether peripheral tail artery and aortic NOS function are differentially regulated by blood pressure in rats with CRF. Using wire myography, arterial function was assessed in 16-week-old Sprague-Dawley rats that were subjected to 5/6 nephrectomy (Nx; arterial ligation model) 8 weeks earlier or non-Nx (control) rats. In aortas from Nx rats, endothelial-dependent vasorelaxation response to acetylcholine (ACh) was blunted and there was enhancement of phenylephrine (PE)-mediated vasoconstriction. Inversely, tail arteries from Nx rats had no change in endothelial function and reduced response to PE. Studies where arterial segments were incubated with the nonspecific NOS inhibitor, L-NAME, showed that Nx reduced NOS function in the aorta but increased NOS function in tail artery for both ACh and PE responses. Furthermore, the observed alterations in NOS function in both aorta and tail artery were abolished when mean arterial blood pressure, as assessed by telemetry, was maintained at normal levels in the 5/6 Nx rats using triple therapy: hydralazine (30 mg/kg per day), hydrochlorothiazide (10 mg/kg per day), and reserpine (0.5 mg/kg per day). In conclusion, differential changes of NOS function in central versus peripheral arteries in CRF are dependent upon hypertension.

Safety and efficacy of local periadventitial delivery of sirolimus for improving hemodialysis graft patency: first human experience with a sirolimus-eluting collagen membrane (Coll-R).

BACKGROUND: Neointimal hyperplasia causes a high rate of hemodialysis synthetic graft failure. Thus, therapies that inhibit neointimal hyperplasia are urgently needed. The Coll-R is a sirolimus-eluting collagen matrix designed for intra-operative perivascular implantation around the graft-venous anastomosis. Sirolimus is an anti-proliferative drug that has proven clinical utility in suppressing neointimal tissue growth in coronary artery disease when delivered locally to the vascular wall by an endovascular drug eluting stent. METHODS: A cohort of 12 chronic hemodialysis patients underwent surgical placement of 13 polytetrafluoroethylene grafts + Coll-R and were followed for up to 24 months. The primary endpoint was safety (freedom from device related adverse events). Secondary endpoints were pharmacokinetics of sirolimus release, success of Coll-R implantation and primary unassisted graft patency. RESULTS: There were no technical failures, infections, vascular anastomotic or wound-healing problems. Whole blood sirolimus levels rose to a mean peak of 4.8 ng/mL at 6 h and fell to <1 ng/mL at 1 week (n = 5). Twelve and 24-month primary unassisted patencies were 76 and 38%, respectively, and the thrombosis rate was 0.37/patient-year. CONCLUSIONS: Perivascular implantation of the Coll-R during graft surgery safely delivered sirolimus to the vascular wall. Systemic sirolimus levels were sub-therapeutic for immunosuppression. This small first-in-human study supports the concept that the Coll-R can safely deliver sirolimus to the graft-venous anastomosis. Safety and patency in this small study were sufficiently encouraging to justify randomized controlled trials to further test the efficacy of the Coll-R.

Vascular access surveillance: an ongoing controversy.

Hemodialysis vascular access surveillance continues to be widely recommended despite ongoing controversy as to its benefit in prolonging access patency compared with clinical monitoring alone. The most common screening tests are access blood flow and dialysis venous pressure measurements. When surveillance test results cross a predetermined threshold, accesses are referred for intervention with correction of stenosis to reduce future thrombosis and prolong access survival. Current surveillance strategies have four components: (1) underlying condition; (2) screening test; (3) intervention; and (4) outcomes. However, limitations exist within each component that may prevent achieving the desired outcomes. This review discusses these limitations and their consequences. To date, randomized controlled trials have not consistently shown that surveillance improves outcomes in grafts, and there is limited evidence that surveillance reduces thrombosis without prolonging the life of native fistulae. In conclusion, current evidence does not support the concept that all accesses should undergo routine surveillance with intervention.

Controversial vascular access surveillance mandate.

The Centers for Medicare and Medicaid Services (CMS) recently revised the requirements that end-stage renal disease (ESRD) dialysis facilities must meet to be certified under Medicare. The CMS ESRD Interpretive Guidance Update states that the dialysis facility must now have an ongoing program of hemodialysis vascular access surveillance. Surveillance usually refers to monthly access blood flow or static dialysis venous pressure measurements combined with preemptive correction of stenosis. However, surveillance as currently practiced does not accurately predict synthetic graft thrombosis or prolong graft life. There is limited evidence that monthly surveillance may reduce native arteriovenous fistula thrombosis without prolonging fistula life, but the effect on thrombosis awaits further confirmation. Thus, the CMS surveillance requirement is not evidence based. We recommend the following changes to the ESRD Interpretive Guidance Update: only monitoring (e.g., physical examination) is required, whereas the proper role of surveillance awaits the results of further research. Such changes would allow nephrologists to apply the clinical judgment and individualized care that is most beneficial to their patients.

Influence of arterial elasticity and vessel dilatation on arteriovenous fistula maturation: a prospective cohort study.

BACKGROUND: Arteriovenous fistula maturation requires dilatation of the anastomosed artery and vein. The factors that affect dilatation and the mechanisms by which dilatation promotes maturation are not understood. This pilot study tested two hypotheses: that low arterial elasticity is associated with maturation failure, and that vessel dilatation is required for adequate fistula blood flow during dialysis. METHODS: Thirty-two patients underwent preoperative measurement of small artery elasticity index, and pre-anastomosis measurement of artery and vein luminal diameters during fistula surgery. Fistulas were considered mature if they were used successfully in three consecutive treatments within 6 months. A mathematical model was used to determine whether vessel dilatation is needed for adequate fistula flow. RESULTS: Six fistulas were excluded from analysis of maturation because dialysis did not begin within 6 months. Twenty-one of the remaining 26 fistulas were located in the upper arm. Six of 26 failed to mature, and all 6 developed stenosis. The average small artery elasticity index was lower in failed than in matured fistulas (2.25 versus 3.71 ml/ mmHg x 100, P = 0.02). Artery and vein diameters of the 32 patients ranged from 2.5 to 5.0 and 3.5 to 7.0 mm, respectively. When the diameters were applied to the mathematical model, predicted fistula flows ranged from 412 to 1380 ml/min. CONCLUSIONS: Low arterial elasticity is associated with stenosis and fistula maturation failure. However, vessel dilatation is not needed for adequate blood flow except at the smaller diameters in this study. We speculate that low elasticity promotes development of stenosis. Larger studies are needed to confirm these promising results and to determine whether therapies directed at improving elasticity can improve maturation.

Risk of hemodialysis graft thrombosis: analysis of monthly flow surveillance.

BACKGROUND: During clinical application of flow surveillance of hemodialysis grafts, the risk of thrombosis is assessed month after month, rather than after one or several measurements, as has been done in published studies. Adequate assessment of risk should consider the many measurements obtained over time. STUDY DESIGN: Prospective cohort diagnostic test study. SETTING & PARTICIPANTS: 176 patients with hemodialysis grafts from 2 university-affiliated dialysis units during a 6-year period. INDEX TESTS: Monthly measurement of graft blood flow or change in flow. OUTCOME: Graft thrombosis. RESULTS: We used logistic regression analysis to compute the risk of thrombosis and used receiver operating characteristic (ROC) curves to assess the accuracy in predicting thrombosis within 1 month. Newer grafts were most likely to thrombose, whereas older grafts were unlikely to thrombose even at low flows or large decreases in flow. Areas under the ROC curves were 0.698 for flow and 0.713 for change in flow measured over 2 months. Flow predicted thrombosis with a sensitivity of 53% at a specificity of 79%, and change in flow had a sensitivity of 58% at a specificity of 75%. More than half the thromboses lacked a change in flow measurement, usually because thrombosis occurred before a change could be measured. Thus, the effective predictive accuracy of change in flow was much less than the ROC curves indicated because the curves do not consider missing measurements. LIMITATIONS: Performance characteristics of index tests may vary across patient populations. CONCLUSION: Flow and change in flow are inaccurate predictors of thrombosis. Many thromboses are not predicted, and intervention based on surveillance likely yields many unnecessary procedures. Thus, this study does not support routine application of surveillance to prevent thrombosis.

Should arteriovenous fistulas and synthetic grafts undergo surveillance with pre-emptive correction of stenosis?

This Practice Point commentary discusses Tonelli et al.'s systematic review and meta-analysis of randomized controlled trials that evaluated surveillance of hemodialysis accesses. Tonelli et al. identified studies that used access blood-flow measurements or duplex ultrasound, and found only four publications of native fistulas and seven of synthetic grafts that met their criteria. Study quality was not high and statistical power was generally low. Tonelli et al. found that fistula surveillance reduced the risk of thrombosis without prolonging fistula life, and that graft surveillance showed no benefit. This commentary discusses why this small meta-analysis might have been biased towards not finding a benefit for stenosis surveillance of grafts by duplex ultrasound. Larger multicenter randomized trials are needed to establish the role of surveillance. Tonelli et al.'s study will encourage reconsideration of the current recommendation in clinical practice guidelines that grafts should undergo routine flow surveillance.

Inflow stenosis obscures recognition of outflow stenosis by dialysis venous pressure: analysis by a mathematical model.

BACKGROUND: Recent studies have shown that inflow stenosis of haemodialysis grafts is more common than previously realized. The influence of inflow stenosis on graft haemodynamics and venous pressure (VP) surveillance has not been previously systematically studied. METHODS: We used a well-established mathematical model to determine the relation between inflow stenosis and static VP (adjusted for mean arterial pressure, VP/MAP), outflow stenosis and artery and vein luminal diameters. We applied low, median and high ratios of artery/vein diameters from 94 patients with grafts. The median ratio was 0.77, indicating that the artery was generally narrower than the vein. RESULTS: The model shows that inflow stenosis reduces VP/MAP. More importantly, however, as outflow stenosis progresses, fixed inflow stenosis causes a delayed increase in VP/MAP followed by a rapid increase at critical outflow stenosis. When both stenoses progress together, their relative rates determine whether and how rapidly VP/MAP increases. The increase in VP/MAP is remarkably abrupt when the rate of inflow stenosis approaches that of outflow stenosis. No increase occurs when inflow stenosis progresses as fast or faster than outflow stenosis. CONCLUSION: Inflow stenosis exerts its most important haemodynamic effect through its interaction with outflow stenosis. As outflow stenosis progresses, inflow stenosis causes a delayed and then rapid increase in VP/MAP at critical outflow stenosis. This increase may not be detected before thrombosis unless measurements are very frequent. Inflow stenosis has an important impact on graft haemodynamics and surveillance because of its location in the relatively narrow inflow tract.

Mathematical model demonstrates influence of luminal diameters on venous pressure surveillance.

BACKGROUND: The reliability of dialysis venous pressure (VP) in detecting stenosis is controversial. A mathematical model may help to resolve the controversy by providing insight into the factors that influence static VP. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: This study used inflow artery and outflow vein luminal diameters from duplex ultrasound studies of 94 patients. These diameters were applied to a mathematical model, and how they affect the relation among VP, mean arterial pressure (MAP), blood flow, and stenosis was determined. Whether VP/MAP is a valid adjustment for the influence of MAP on VP, and whether the standard VP/MAP referral threshold of 0.50 is valid, were also determined. RESULTS: It was found that there is an approximate one-to-one relation between MAP and VP, so VP/MAP is a valid adjustment. Also, the 0.50 threshold successfully identifies most grafts with stenosis of 65% or more. However, the ratio of artery/vein diameters varied widely between patients, and the ratio independently influences VP/MAP. When the inflow artery is relatively narrow, the VP/MAP increase is delayed followed by a more rapid increase as critical stenosis is reached. CONCLUSIONS: VP/MAP is a valid adjustment for the influence of MAP on VP, and the standard VP/MAP threshold of 0.50 warns of the transition to critical stenosis. However, relatively narrow arteries cause a delay followed by a rapid increase in VP/MAP that may not be detected before thrombosis unless measurements are very frequent. Clinical trials that emphasize trend analysis with frequent measurements are needed to evaluate the efficacy of VP surveillance.

Influence of luminal diameters on flow surveillance of hemodialysis grafts: insights from a mathematical model.

Randomized controlled trials have not shown that surveillance of graft blood flow (Q) prolongs graft life. Because luminal diameters affect flow resistance, this study examined whether the influence of diameters on Q can explain the limitations of surveillance. Inflow artery and outflow vein diameters were determined from duplex ultrasound studies of 94 patients. These diameters were applied to a mathematical model for determination of how they affect the relation between Q and stenosis. Also determined was the correlation between Q (by ultrasound dilution) and diameters, stenosis, and mean arterial pressure in 88 patients. Artery and vein diameters varied widely between patients, but arteries generally were narrower than veins. The model predicts that the relation between Q and stenosis is sigmoid: as stenosis progresses, Q initially remains unchanged but then rapidly decreases. A narrower artery increases flow resistance, causing a longer delay followed by a more rapid reduction in Q. In a multiple regression analysis of data from patients, Q correlated with artery and vein diameters, sum of largest stenoses from each circuit segment, and mean arterial pressure (R = 0.689, P < 0.001). This study helps to explain why Q surveillance predicts thrombosis in some patients but not others. Luminal diameters control the relation between Q and stenosis, and these diameters vary widely. During progressive stenosis, the delay and then rapid reduction in Q may impair recognition of low Q before thrombosis occurs. Surveillance outcomes might be improved by taking frequent measurements so that there is no delay in discovering that Q has decreased.

Mathematical model for pressure losses in the hemodialysis graft vascular circuit.

Stenosis-induced thrombosis and abandonment of the hemodialysis synthetic graft is an important cause of morbidity and mortality. The graft vascular circuit is a unique low-resistance shunt that has not yet been systematically evaluated. In this study, we developed a mathematical model of this circuit. Pressure losses (deltaPs) were measured in an in vitro experimental apparatus and compared with losses predicted by equations from the engineering literature. We considered the inflow artery, arterial and venous anastomoses, graft, stenosis, and outflow vein. We found significant differences between equations and experimental results, and attributed these differences to the transitional nature of the flow. Adjustment of the equations led to good agreement with experimental data. The resulting mathematical model predicts relations between stenosis, blood flow, intragraft pressure, and important clinical variables such as mean arterial blood pressure and hematocrit. Application of the model should improve understanding of the hemodynamics of the stenotic graft vascular circuit.

Vascular access as a determinant of adequacy of dialysis.

Vascular accesses consist of permanent arteriovenous (AV) accesses (autogenous fistulas and synthetic grafts) and venous accesses (central venous catheters [CVCs]). AV accesses have fewer complications than venous accesses, and are therefore the preferred hemodialysis access. An important additional issue is whether the type of access influences adequacy of dialysis (i.e. Kt/V). Key limiting factors in delivering adequate Kt/V are blood pump speed (Q(B) ), access recirculation, and treatment time. In general, AV accesses support higher Q(B)S with less negative inflow arterial pressures than CVCs. Well-functioning AV accesses are also less likely to exhibit recirculation. Nevertheless, recirculation commonly develops when AV accesses (usually grafts) develop stenosis with decreased access blood flow. Although extension of treatment time can offset the effects of reduced Q(B) and recirculation, this is often impractical and poorly accepted by patients. In conclusion, AV accesses are superior to venous accesses because they are less prone to complications and are more likely to deliver prescribed Kt/V within prescribed treatment time.