Role of Vascular Access as a Risk Factor for Infections in Hemodialysis

Abstract

Infections are a major cause of morbidity and mortality in chronic hemodialysis patients. This single center prospective study was carried out to determine the incidence and risk factors for infection in hemodialysis patients and plan appropriate strategies to reduce the risk of infection. A total of 84 consecutive patients who were initiated on hemodialysis over a 2-year period were followed until they either received a kidney transplant or died. In our hospital, as a policy, patients are offered hemodialysis as a bridge therapy to a kidney transplant. The mean duration of follow up was 3 months (range 1–11.8 months). The factors associated with at least one episode of infection were evaluated. Statistical analysis was done by multivariate stepwise logistic regression method. Fifty-one patients had a total of 57 episodes (67.8%) of infection. Of the 44 episodes of acute bacterial infections, vascular access exit site infection was the commonest followed by septicemia (13 patients, 29.5%). Staphylococcus aureus was the commonest bacterial isolate observed in 14 patients. On multivariate analysis, three risk factors for infection were identified: (1) nonarteriovenous fistula (AVF) vascular access for hemodialysis (p = 0.02), (2) increased number of hemodialysis sessions (p = 0.03), and (3) lower serum calcium level (p = 0.02). NonAVF vascular access was found to be the most important risk factor for infection in hemodialysis patients. Creation of an AV fistula, preferably at an early stage, appears beneficial for minimizing the risk of infection even in patients who are on short-term hemodialysis as a bridge therapy towards a kidney transplant.

• Hemodialysis
• Infections
• Morbidity
• Mortality
• AV fistula

Introduction

Infections are a major cause of morbidity and mortality in chronic hemodialysis patients. Several risk factors for bacterial infection in chronic long-term hemodialysis patients have been identified or suggested. These include a history of infection,[[1]] use of a central venous catheter for dialysis rather than an arteriovenous fistula,[[2]], [[3]] Staphylococcus aureus nasal carriage,[[4]] hypoalbuminemia,[[5]] and iron overload.[[6]] However, most of these studies have involved patients on long-term maintenance hemodialysis. In developing countries like India, availability of hemodialysis facilities is limited because of economic constraints. Hence, most of these patients receive a short-term hemodialysis as a bridge therapy towards a renal transplant.[[7]]

It is a common observation in hemodialysis that incidence of infection with central venous catheter increases with its longer use. Similarly hypoalbuminemia and iron overload are problems seen more commonly with long-term hemodialysis. Thus there is a possibility that the relative significance of these factors for predisposing infection may be different in the situation where dialysis is required for a much shorter period. This observation is relevant as this may help in planning the strategy to minimize infections in patients on short-term hemodialysis in contrast to those on long-term hemodialysis. We therefore undertook this prospective study to find out the factors predisposing to microbial infections in patients on short-term hemodialysis, and to plan strategies to minimize the risk of these infections.

Patients and Methods

We followed 84 consecutive end-stage renal disease (ESRD) patients on hemodialysis over a 2-year period. Primary endpoint was occurrence of a bacterial infection. In our unit, as a policy, only those patients are accepted in the hemodialysis program who are planned to receive a kidney transplant. These patients undergo a 5-h session of hemodialysis treatment twice a week. For the purpose of this study, we included only those patients who had a minimum of 4 weeks of hemodialysis treatment, i.e., 8 sessions of hemodialysis. These patients were followed up until they exited from hemodialysis program, i.e., either received a transplant or died.

Of the 84 patients, 4 (4.8%) patients were dialyzed through arteriovenous shunts (AVS) only, 19 (22.6%) through arteriovenous fistula (AVF) only, while 61 (72.6%) had a combination of both i.e., they were initially dialyzed through a temporary vascular access (AVS or femoral catheter or internal jugular catheter) followed by AVF. All of them were HIV negative. Four of the 84 patients were HBsAg positive (4.2%) prior to initiation into the dialysis program, while 80 were HBsAg negative and vaccinated for hepatitis B. Dialyzer and tubing were reused in all patients except for those who were HBsAg or anti-HCV seropositive. Blood transfusions were administered in 64 patients, while 20 received recombinant erythropoietin.

All these patients were subjected to the following monthly investigations: hemoglobin, total leukocyte count, peripheral smear for type of anemia, serum total protein, albumin, calcium, phosphorus, alkaline phosphatase, serum glutamic pyruvate transferase (SGPT), serum glutamic oxaloacetate transferase (SGOT), HIV, blood urea nitrogen, serum creatinine, sodium, and potassium. Anti-HCV antibodies testing was done only if the patients developed elevated liver enzymes. Adequacy of dialysis was monitored by monthly measurements urea reduction ratio (URR). The dialysis prescription was targeted to achieve a URR of 65%. Patients were monitored for the occurrence of infections clinically and by the following laboratory investigations: urine culture, blood culture, chest X-ray, pleural and ascitic fluid analysis (total and differential cell count, Gram's stain, ZiehlNeelsen stain, bacterial and tubercular culture, and protein and glucose content of fluid), pus swab culture from vascular access exit site, fungal blood culture, HBsAg and HIV. Fine needle aspiration and cytology, and biopsy of lymph nodes were done when indicated. The time of patient's death or renal transplant was recorded.

Case Definitions

Urinary tract infection was defined as presence of bacterial count ≥10⁵ CFU/mL in a midstream urinary specimen. Definitive sepsis was defined as isolation of a single species of bacteria. Presumptive sepsis was defined as presence of high-grade fever and raised total leukocyte count in the absence of localizing evidence, i.e., negative blood and urine culture, and normal chest x-ray. Pneumonitis was defined as the presence of radiological opacity on plain chest x-ray along with appropriate clinical features.

Statistical Analysis

In order to evaluate the factors predictive of increased risk of infections in these patients, univariate analysis was carried out initially. Chi-square test was used for discrete variables such as: type of underlying disease, presence of fluid overload, HBsAg seropositivity, pericarditis and gender. Student's t-test was used for analyzing continuous variables such as: age, number of blood transfusions, total number of hemodialysis sessions, dry weight, number of hemodialysis sessions via different vascular accesses (AVF vs. nonAVF accesses), hemoglobin, serum calcium, phosphate, total protein, albumin, SGOT, and SGPT. In the second stage, a multivariate analysis was carried out by the forward stepwise logistic regression method using the SPSS statistical program for Windows (Il, USA, 1998) with the outcome variable being the occurrence of bacterial infections.

Results

Of the 84 patients studied there were 70 men and 14 women. The mean age of patients was 38.2 ± 10.4 years. The mean number of hemodialysis treatments was 24 ± 15 (8–94). Of the 84 patients, 2 died and the 82 received living related renal allograft.

Of the 84 patients, chronic glomerulonephritis (CGN) was the commonest cause of ESRD in 60 (71.4%) patients, followed by diabetic nephropathy (DN) in 10 (11.9%), chronic interstitial nephritis (CIN) in 7 (8.3%), hypertensive renal disease in 6 (7.1%), and acute cortical necrosis in 1 (1%) patient. The cause of ESRD was diagnosed as per case definitions described in an earlier study.[[8]] The mean dry weight of these patients was 51.5 ± 9.8 kg. Twenty-two (26.2%) of these patients had at least one episode of pulmonary edema. Seven patients developed pericarditis while on hemodialysis. Majority of our patients (65 out of 84, 77.3%) presented to us with ESRD, requiring immediate placement of a temporary access (AV shunt or central venous catheter) for hemodialysis. These patients had 41 episodes of bacterial infections. The maximum number of hemodialysis treatments was carried out through AVF (mean 18.8 ± 16.6) followed by AVS (7.5 ± 3.5), internal jugular 4.6 ± 3.7 and femoral access (2.4 ± 1.6).

On analyzing the spectrum of infections, we observed that 67.6% (51/84) of these patients had one or more episodes of infections. There were 57 episodes of infections, of which the commonest were acute bacterial infection in 44 (77.2%) patients, followed by tuberculosis in 8 (14%), and acute viral hepatitis in 5 (8.8%). None of the patients developed HIV or fungal infections. Of these 84 patients, 2 patients died, both due to septicemia.

Of the 44 episodes of acute bacterial infections, vascular access infection was the commonest in 14/44 (31.8%) episodes (AVS = 12, AVF = 1, and jugular catheter = 1). There were 13 episodes of septicemia, 3 of them associated with local AVS infection. These infections were common in patients who had AVS and IJ catheters rather than AVF as vascular access. Amongst the other infections, there were 7 episodes (15.9%) of urinary tract infection (UTI), 5 episodes of pneumonitis (11.3%), and 5 episodes (11.3%) of miscellaneous infections (acute gastroenteritis in 3, and abscess and peritonitis in 1 each). Of the 34 episodes of culture positive bacterial infections, Staphylococcus aureus was the predominant organism accounting for 16 episodes (47%), followed by E. coli in 10 (29.4%), and Pseudomonas aeruginosa in 4 (11.7%). Of the rest 4 isolates, Acinetobacter loeffli, Citrobacter sp., Enterobacter sp., and Enterococcus faecalis accounted for 1 each.

On univariate analysis, the factors predictive of the occurrence of bacterial infections were: (i) lower dry weight (p = .06), (ii) low serum calcium (p = 0.009), (iii) low serum phosphate (p = 0.04), and (iv) use of nonarteriovenous fistula as vascular access (p = 0.01). On analyzing the factors predictive of acute bacterial infections only, the following factors were observed to be significant: (i) increased number of hemodialysis treatments (p = 0.03), (ii) nonAV fistula vascular access for hemodialysis (p = 0.02), and (iii) a low serum calcium (p = 0.02).

Discussion

The incidence of bacterial infections (67.6%) in our study is higher than that reported by others.[[1]], [[2]] However, the incidence of septicemia (29.5%), is lower than that reported by Nielsen et al (49%). The incidence may not have been truly that low as the frequency of blood cultures done was quite different in our study. We carried out blood culture only in patients symptomatic of sepsis while Nielsen et al. carried out protocol blood cultures at weekly intervals. Thus we could have missed out subclinical bacteremic episodes. Also 22.6% of our patients were dialyzed exclusively through native AV fistula. Two of 84 patients died of septicemia, an incidence very similar to that reported by Nielsen et al.[[9]]

Vascular access exit site infection was the commonest one accounting for 31.8% (14/44) of all infections. Most of these patients with infection (12 out of 14) had arteriovenous shunt (AVS) as access. In sharp contrast, just one patient with arteriovenous fistula (AVF) developed an access site infection. This too was a fistula converted from AV shunt. Even other bacterial infections like urinary tract infection, pneumonitis, gastroenteritis, and septicemia were all seen predominantly in patients with nonAVF vascular access for hemodialysis. Only 3 patients out of 19 (15.8%) who were dialyzed exclusively through AVF got any bacterial infection. In contrast, 41 episodes of bacterial infections were noted in 65 patients (63.07%) who were dialyzed through nonAVF access for any length of time. This difference was statistically significant. This points toward the overwhelming importance of nonAVF vascular access, being a strong risk factor for the development of infection in patients even on short-term hemodialysis. Most of our chronic renal failure patients are referred quite late for dialysis and transplant. Thus hemodialysis has to be started through a nonAVF vascular access such as arteriovenous shunt or central venous catheter or femoral venous catheter. AV fistula is usually created later on.

Strict comparison of arteriovenous shunt infection is not possible because the practice of making AVS for temporary vascular access is almost nonexistent now. However, analogy can be drawn between central venous hemodialysis catheter and arteriovenous shunt, both being made up of foreign material and providing a communication from exterior to vascular lumen. Many studies are available and almost all point towards overwhelming importance of dialysis catheter as the greatest risk factor for infection in hemodialysis patients[[1]], [[2]], [[3]], [[10]], [[11]] Almirall et al. looked into the mechanism of infection in hemodialysis catheters.[[12]] Catheters provide the portal of entry of bacteria, which subsequently colonize the catheter. A bacterial film on the luminal surface of catheter then forms. This colonization often leads to bacteremia. The time period between insertion of catheter and colonization by bacteria varies, but is universally present after 16 weeks.[[9]] Late colonization of AVS or dialysis catheter may be an explanation for comparatively lower incidence of septicemia in our series as mean duration of hemodialysis was three months only and many patients got dialysis for even shorter duration. Also increased number of hemodialysis treatments or longer duration of dialysis emerged to be a significant risk factor for infection. This again can be explained by the increasing incidence of bacterial colonization of hemodialysis catheter with time. Progressive malnutrition and anemia may also contribute.

The adverse consequences of dialysis catheter infection are well known. Apart from increased morbidity and mortality of patients, requirement for frequent changes of catheter increases the cost of dialysis.

Various strategies for prevention as well as early detection and treatment of catheter infection have been suggested. These include observance of strict aseptic measures, decolonization of the nostrils by rifampicin, and intranasal mupirocin or povidone iodine,[[13]] and use of antibiotic coated catheters.[[14]] Timed blood cultures and newer technique such as use of endoluminal brush culture has been suggested to help in early detection of infection. However, none of these approaches seem to be fool proof.

The incidence of access site-related infections was minimal in patients with native AV fistula. This offers an excellent way out to nearly eliminate at least access site- associated infections. Longer survival of vascular access and reduced cost are additional bonus. Thus early creation of an arteriovenous fistula can perhaps be one of the most effective strategies for prevention of infection in hemodialysis patients. This approach finds favor with the recommendations of DOQ1,[[15]] DOPPS study[[16]] as well as the study by Schwab.[[17]]

The third significant factor predictive of bacterial infection in hemodialysis on multivariate analysis was a lower serum calcium level in our study. To the best of our knowledge, this is the first study to suggest that low serum calcium level could be a risk factor for infection in hemodialysis patients. We do not have a good explanation to offer for this finding. Could this possibly be due to interference with calcium-dependent immune activation of T cells, we can only speculate at the moment.

Conclusion

Longer duration on hemodialysis therapy and lower serum calcium levels are significant risk factors for infection in chronic hemodialysis patients. But the most important risk factor remains nonAV fistula vascular access for hemodialysis—be it arteriovenous shunt or central or femoral venous catheter. Timely creation of a native arteriovenous fistula appears to be the most effective way to minimize infections in hemodialysis patients. This will reduce morbidity and mortality of patients on hemodialysis, besides being more cost effective. Thus there may be a need for creating greater awareness amongst the primary care practitioners for early referral to a nephrologist.