The Nitric Oxide Problem: Can Proton Pump Inhibitors Delay Fistula Maturation?

doi:10.21203/rs.3.rs-2460778/v1

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The Nitric Oxide Problem: Can Proton Pump Inhibitors Delay Fistula Maturation?

https://doi.org/10.21203/rs.3.rs-2460778/v1

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INTRODUCTION: We have previously shown that the position and presence of a hemodialysis catheter will delay maturation of the first fistula created for hemodialysis patients. Since that publication it has been suggested that the use of a proton pump inhibiter will adversely affect endothelial function. We therefore re-examined our data base to determine of the adverse effect of proton pump inhibiters on the endothelial would also delay fistula maturation.

METHODS: This was the re-examination of a database from a prospective observational study of 808 patients who underwent the creation of an autologous arteriovenous fistula for their first hemodialysis access who were evaluated for the length of use of a temporary catheter. The variables studied for their effect upon catheter use included: location in the forearm or upper arm, age, the presence of diabetes, vascular disease or smoking history. To those variables we added the use of a proton pump inhibiter.

FINDINGS: For upper arm fistulas, the use of a proton pump inhibiter appeared to delay upper arm fistula maturation (p=0.01) but not forearm maturation when in the presence of a long-term dialysis catheter (p=0.44).

DISCUSSION: Proton pump inhibiter use may adversely affect or delay fistula maturation, but further study is needed.

Since annual hospital costs and morbidity are much lower with fistulas than either grafts or catheters,[1] fistulas remain the preferred access for hemodialysis. Unfortunately one group of investigators found only 21% of the fistulas had matured sufficiently by 90 days to have any dialysis catheter removed.[2] After the publication of our work which found that upper arm fistulas tended to develop faster than forearm fistulas and both were delayed if the maturation occurred in the presence of a long-term indwelling hemodialysis catheter[3], other investigators have found that proton pump inhibiters (PPI) induce endothelial dysfunction.[4]Although we have previously examined the effects of a vast array of medications on fistula patency, we had not examined the effect of PPIs.[5-7]Since the maturation of fistulas depends upon a flow induced release of nitric oxide[8-10] (Figure 1),we chose to re-examined our database to see if the presence of a PPI had any effect over and above those we have previously reported.

This was the re-examination of a database from a prospective observational study of 808 patients from 7/1/2004 through 6/30/2014 who underwent the creation of an autologous arteriovenous fistula for their first hemodialysis access who were evaluated for the length of use of a temporary catheter. The variables studied for their effect upon catheter use included: location in the forearm or upper arm, age, the presence of diabetes, vascular disease [4] or smoking history. To those variables we added the use of a proton pump inhibiter. Vascular disease was defined by any known history of peripheral, coronary or cerebrovascular disease that had been diagnosed by x ray, contrast angiography, doppler flow studies or at surgery. Because an intraoperative blood flow that is less than 120 cc/min is associated with fistula failure to mature, assurance that the flow was above that level was attempted before closure in the operating room. Since each patient's fistula was his first vascular access, no patient was treated with any anticoagulation for their vascular access, particularly given our experience with the lack of effect on maturation and fistula patency of that class of medications; however, although no patients were treated with warfarin, a few patients with atherosclerotic coronary and cerebrovascular disease were already being treated with aspirin or other antiplatelet agents at the time of their surgery and these were recorded[3-5]. Statistical analysis for normality, and analysis of variance were performed.

In Compliance with Ethical Standards: As the work was purely observational by the physicians following the patients after renal failure began and no treatment intervention was either given or withheld by the observers, no other approval was necessary.

Eight hundred and eight patients who began hemodialysis treatments between 7/1/2004 and 6/30/2014 underwent the creation of an autologous arteriovenous fistula as their first vascular access and Table 1 lists the characteristics of all variables analyzed. The results of the effect of location and presence of a catheter have been previously reported by us [1] and readers should refer to our previous work for full details, but some of the details are listed in Table 1. Our new analysis concerns the whether a PPI had any effect upon maturation rates. Of all those 808 patients, 281 patients (34.8%) were treated with a PPI at the time of fistula creation. Of the five hundred and seventy-eight patients with fistulas that were placed in the upper arm, 201 (34.1%) were treated with a PPI while 84 (36.6%) patients who had their fistula placed in the forearm were treated with a PPI(P=0.19). Two hundred and fifty-nine (44.4%) of the upper arm group were placed prior to catheter insertion while 106 (46.4%) of the 230 patients in the forearm group had surgery prior to catheter insertion (P=0.34). Four hundred and fort-three patients had a catheter placed before a fistula was created. All fistulas were placed on the contra-lateral side to the catheter when a catheter was already present or being simultaneously placed

When the fistula was created in the presence of an indwelling vascular hemodialysis catheter, the use of a PPI made no significant difference in maturation time (p=0.83); however, if the fistula was placed prior to the insertion of an indwelling hemodialysis catheter, the maturation rate was significantly delayed in patients using a PPI (p=0.02), particularly in the first 40 days after surgery Figure 2. The effect was predominantly seen in the faster maturing upper arm fistulas (p=0.01), and was not seen in the slower maturation times of the forearm fistula (p=0.46).

After the creation of an arteriovenous connection, there is an increase in blood flow, which results in vasodilatation through upregulation of cyclooxygenase and nitric oxide synthase in endothelial cells which catalyze the synthesis of prostacyclin and nitric oxide. PPIs are known to impair nitric oxide (NO) by elevating concentrations of NO synthetase inhibiters (NOSi) such as asymmetrical dimethylarginine (ADMA) (Fig. 3),[11] which impairs nonenzymatic formation of nitric oxide [4]. Since it is well known that NO is essential for fistula maturation [8–9] (Fig. 1), we examined the possibility that PPIs may interfere with vascular access development.

Even after our analysis, it remains unclear as to the magnitude of the effect of PPIs on fistula development. It is not surprising that the chronic inflammation of an indwelling vascular hemodialysis catheter might be associated with delayed maturation and decreased NO production since NOSi are regularly used to control inflammation [12] and therefore the lack of an additional effect by PPIs might be expected. Lack of an effect in forearm fistulas may be more difficult to explain. Despite being less likely to be diabetic or have known vascular disease this location is already known to have a slower maturation rate that has been thought due to lower shear stress resulting from smaller caliber blood vessels. Perhaps, the slower maturation rates of catheter patients and forearm fistulas are not as dependent upon the production of large quantities of nitric oxide. Two previous studies have evaluated whether ADMA was associated with fistula stenosis or thrombosis and they are conflicted [13, 14]. The first study which had much lower levels of ADMA than the second demonstrated that lower levels of ADMA were associated with restenosis [13]. The second which found much higher levels measured ADMA levels at the time of fistula creation did not result in higher rates of thrombosis or stenosis in 60 patients; although the cumulative index of thrombosis was more than double in patents with above median ADMA at 200 days [14]. That number did not reach statistical significance, however. Furthermore, the time to maturation was not correlated to those levels [14]and indeed their time to maturation was over twice as long for their fastest maturation as the length of time for 100% maturation in our data for upper arm fistulas with no catheters. We evaluated a totally different association. We believe that inflammatory pathways are more important in stenosis and thrombosis, but dilatation and increased blood flow rate from NO more important in maturation. Since we found no association for the slower rates associated with forearm fistulas and catheters, we would not have been surprised that their times to maturation were unaffected by ADMA levels since their maturation times were much slower and more comparable to our patients with catheters and forearm fistulas.

Recently, PPIs have been found to be more harmful in dialysis patients than previously thought. While the vascular calcification they cause [15] may not be associated with increased access failure [16], the increased mortality associated with PPI use [17] in dialysis patients cannot be ignored. There should be further investigation into the detrimental and therapeutic effects that cannot be answered by this study.

While the study has the benefit of a single center with adequate cases, it is limited by being a retrospective ad hoc analysis of previous data. Therefore, while it appears that PPIs might be able to inhibit the rapid maturation of upper arm fistulas in patients who do not have an indwelling vascular catheter, we suggest further randomized controlled studies to determine the effect of PPIs on fistula maturation.

REQUIRED STATEMENTS:

Neither this paper nor any of the details of this study have been submitted elsewhere and it has never been under review by another journal nor has it been published previously. No author has any conflict of interest and all the authors are aware of and approve the manuscript as submitted to this journal. In Compliance with Ethical Standards: As the work was purely observational by the physicians following the patients after renal failure began and no treatment intervention was either given or withheld by the observers, no other approval was necessary

Ethical Approval

As this was merely a statistical analysis of our previously published work no ethical board review was necessary.

Consent to Participate

Not Applicable

Consent to Publish

Not Applicable

Competing interests

None

Authors' contributions

CHARLES J. DISKIN M.D.: Conception Design and Analysis

LINDA M. DANSBY M.D.: Data Collection and Review

THOMAS B. CARTER D.O.: Data Collection and Review

LAUTREC RADCLIFF M.D.: Data Collection and Review

CHARLES D. DISKIN M.D. : Data Collection and Review

Funding

None

Availability of data and materials

Data Available on request and in Prior publication

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Table 1

There appeared to be a delay in fistula maturation in patients taking PPIs, but the effect was found only in patients who had upper arm fistulas and did not have an indwelling dialysis catheter.
	UPPER ARM	FOREARM	SIGNIFICANCE
SEX % FEMALE	48%	36%	P = 0.009**
RACE %AFRICANAMERICAN	75%	75%	P = 0.46
AGE MEDIAN YEARS	60	55	P < 0.0001***
% SMOKER	60%	56%	P = 0.15
% DIABETIC	62%	45%	P < 0.0001***
% VASCULAR DISEASE	64%	42%	P < 0.0001***
% ANTIPLATELET	17.3%	10.1%	P = 0.002 **
MEDIAN BMI (kg/m2 )	26	26	P = 0.19
MEDIAN DAYS CREATED PRIOR TO DIALYSIS	161	261	P = 0.03*
MEDIAN eGFR at SURGERY (ml/min/1.73 m2 )	9.8	10.1	P = 0.15
SURGERY PRIOR TO CATHETER (%)	44%	46%	P = 0.34
CATHETER USE %	57%	74%	P < 0.0001***
MEDIAN DAYS OF CATHETER USE	70	182	P < 0.0001***
PPI USE	34.1%	35.6%	P = 0.26

No competing interests reported.

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The Nitric Oxide Problem: Can Proton Pump Inhibitors Delay Fistula Maturation?

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