Chronic kidney disease (CKD) is a worldwide public health problem, due to the continuous increase in the number of patients. The rising prevalence of CKD is due especially to the increasing number of patients with diabetes mellitus (DM) and high blood pressure (HBP), which are the major risk factors of the disease. Besides inducing the risk of CKD, HBP may also be the consequence of CKD, occurring in most patients sooner or later in the evolution of the disease (1-3).

Irrespective of the etiology of CKD, the progressive loss of kidney functions has a strong impact on the health status of the patient and renal replacement therapy (RRT) by dialysis (hemodialysis or peritoneal dialysis) or kidney transplant, which is the necessary treatment for advanced stage CKD (4,5).

The infection risk in hemodialysis patients is considerable, explained by impaired immunity and by the need for frequent hospitalizations and surgical interventions. Moreover, hemodialysis itself involves frequent and/or prolonged exposure to blood by means of vascular access and the extracorporeal circuit, and by the proximity of other patients during dialysis, contact with the medical staff, and change of the dialysis machine. The infection with hepatitis C virus (HCV), a particular type of blood-borne viral infection, is relatively common in hemodialysis patients (6).

The association of chronic hepatitis with HCV with an increased morbidity-mortality of the transplanted and the hemodialysis patients is described in numerous studies in the specialized literature. Moreover, statistical studies show a prevalence of infection among CKD patients between 5 and 60% (in developed countries) with certain predominance in patients with chronic hemodialysis patients (7-9). In addition, the data available until 2006 confirm the increased incidence of HCV worldwide, 1.47 per 100 patient-years with a clear difference between developed and poorly developed countries (10,11).

The predominance among hemodialysis patients is supported by numerous studies in the specific literature (12,13). Despite development of prevention guidelines, the risk of transmission of the virus has not been substantially reduced. This justifies the need to increase the education of the medical staff and the patients in order to learn the rules of prevention of HCV transmission in the hemodialysis center (14-18). At the same time, in order to prevent the transmission of the infection, it is necessary to know the immunological status of the patients. Thus, the periodic check-up and screening of patients is especially important because most patients do not present clinical symptomatology suggestive for HCV infection (19).

Demographic factors have an inconsistent role in the predominance of HCV, lowest percentage is found in Northern Europe, while the highest incidence is in Central and East Asia and North America. US has 1.6% while in the rural areas of Romania HCV prevalence is up to even 3% (20). HCV is responsible for ~10% of acute hepatitis cases, 75-85% of chronic hepatitis cases, and ~10-20% will develop liver cirrhosis over 20-30 years (20-22). Among patients with cirrhosis, there is: 1-5% annual risk of hepatocellular carcinoma and 3-6% annual risk of hepatic decompensation, for which the risk of death in the following year is 15-20% (20-22). It is estimated that worldwide 71 million individuals are infected with HCV, a great number of patients dying each year of HCV-related complications (23). HCV infection becomes chronic in a considerable proportion of patients (~75% of cases) (23). Among these, 27% are diagnosed with liver cirrhosis and 25% with liver carcinoma, 20 years after acquiring the infection (23,24).

The prevalence of HCV virus in US hemodialysis (HD) centers (2002 statistical data) has been estimated at ~8% and is higher compared to the general population (25,26). The increased prevalence of chronic hepatitis with HCV in the HD centers was also maintained in the analysis carried out in Europe (27,28). In this context, we emphasize that these observations are valid also in Romania. Comparing with the general population, studies in the literature also describe for Romania a higher prevalence of HCV virus among chronically hemodialysis patients. Despite efforts to improve the methods of preventing the transmission of HCV infection, in Romania both the incidence and the prevalence of the infection are still at an increased rate in chronic hemodialysis patients (29).

HCV was discovered in 1989 and is an RNA virus, member of the Hepacivirus genus, belonging to Flaviviridae family, which is divided into three species: Flavivirus, pestivirus and hepacivirus (30). It is ~30-80 nm in size and has a predominantly lipid content (31). HCV is currently classified into six major genotypes, which differ from each other by >30% at the nucleotide level, as well as numerous subtypes (655) (32).

HCV is transmitted predominantly by contact with blood or infected blood products: Transfusions, use of unsterilized needles and syringes often passed from one person to another, tattoos or vaccinations with unsterilized equipment, sharing of toothbrushes, shaving devices, pincers or manicure toolkits. HCV is also found in bodily fluids (saliva, mother's milk, vaginal secretions, seminal fluid, etc.), but in lower concentrations than hepatitis B virus (HBV). HCV can also be transmitted from mother to fetus (33,34). Vertical transmission rate in anti-HCV positive pregnant women has been estimated as 2.7-4.4%, and as high as 5.4-8.6% for pregnant women with HCV-human immunodeficiency virus (HIV) coinfection (35).

Besides liver involvement, extra hepatic manifestations of chronic HCV infection are common, including kidney involvement. The histopathological spectrum of CKD induced by HCV infection includes membrane-proliferative glomerulonephritis, IgA nephropathy, focal segmental glomerulosclerosis, fibrillary glomerulonephritis, tubulointerstitial nephropathy and thrombotic microangiopathy. The most frequent transmission route of HCV is exposure to infected blood - consequently, hemodialysis patients are at a high risk for infection (23,36), resulting in a higher prevalence of HCV infection than in the general population (37). It has been shown that infection risk increases with the duration of hemodialysis (23,36).

In patients on chronic hemodialysis, HCV positivity is associated with poorer survival (38), the risk of liver disease-related death being compounded by the higher risk of cardiovascular death attributed to chronic malnutrition and inflammation (37,39,40).

The need for early diagnosis and treatment of HCV infection in chronic hemodialysis patients calls for improved screening (17). In US, recent studies have revealed a 5% prevalence of HCV infection in patients on chronic hemodialysis compared to 1% in the general population (41). Romania is among the countries with a high prevalence of HCV infection (~6%) in the general population (42). Furthermore, the prevalence of HCV positivity in chronic hemodialysis patients is high, reaching 50% in some centers (29,42). These facts impose early detection of HCV infected patients and the application of methods for preventing infection transmission within the dialysis center (11,37).

According to the American Association for the Study of the Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) there are categories of individuals more exposed to the risk of HCV infection and in whom testing for the infection is recommended (41). Among them should be counted patients on chronic hemodialysis, and intravenous or intranasal drug users, patients who received a transplant before July 1992, previous prison inmates, and individuals with documented HIV infection. Testing for HCV infection is also recommended for at-risk individuals, namely in persons who suffered puncture injuries by needles or other sharp objects possibly contaminated, as well as in people born between 1945-1965(41). The higher prevalence of HCV infection in CKD patients compared to the general population and the rapid evolution to more advanced stages in the presence of HCV infection justify the need for screening in these patients (43).

For patients on chronic hemodialysis, testing for HCV infection is performed when RRT is initiated or when the patient is transferred from another dialysis center, or when the RRT method is changed (from peritoneal dialysis to hemodialysis), as well as periodically, every six months (43).

The diagnosis of the HCV infection calls for two categories of laboratory tests: Serological tests for anti-HCV antibodies detection and molecular tests for viral particles detection (44-46).

This approach is also appropriate for the diagnosis of HCV infection in chronic hemodialysis patients (Fig. 1). There is a time lapse between the time of HCV infection and the antibody detection in blood. This time span, called ‘serological window’ varies from patient to patient. The currently available serological tests allow for anti-HCV antibodies detection on average 7-8 weeks after the moment of the infection. After eradication of the infection, anti-HCV antibodies may have a lifelong persistence or their titer may progressively decrease until disappearance in several years. In patients with chronic infection, anti-HCV antibodies may persist indefinitely. If currently available laboratory tests yield positive results, confirmation by a supplementary test is necessary, namely recombinant immunoblot assay (RIBA) which indicates the reactivity against two viral antigens. As the screening tests and molecular techniques improve, confirmation by RIBA will become increasingly less necessary (except blood banks). Testing for HCV-RNA [by polymerase chain reaction (PCR)] confirms the diagnosis and quantifies the number of viral copies in the blood (viremia). Almost all patients with chronic infection have HCV-RNA detectable in blood (34,47).

In each patient who started on hemodialysis, testing for anti-HCV antibodies and assessing of liver transaminases (especially alanine transaminase) is recommended. Detection of anti-HCV antibodies does not make the distinction between current and past infection. HCV-RNA detection is necessary to confirm the diagnosis of active HCV infection (47). In contrast to anti-HCV antibodies, which may be detected in the blood 7-8 weeks after exposure, testing for HCV-RNA may detect HCV infection 1 week after exposure.

As there are several HCV genotypes and the specific treatment depends on the genotype, genotype identification is important. However, direct antiviral medication, which inhibits viral replication, covers several HCV genotypes, so that genotype specification does not have to be included in the diagnosis and treatment protocol of the infected patient (48).

The patients on chronic hemodialysis are usually tested for anti-HCV antibodies and for the serum level of alanine-transaminase (ALT). In the dialysis centers with a high prevalence of HCV infection, initial testing for HCV-RNA is recommended (43).

The patients in whom anti-HCV antibodies are detected should also be tested for HCV-RNA. In the patients with undetectable HCV-RNA levels, cured spontaneously or after antiviral treatment, testing should be performed every six months. In the positive patients for anti-HCV antibodies and with detectable HCV-RNA, declaring the infection and applying the specific treatment are mandatory (49).

For patients in whom HCV screening detects no infection, monitoring ALT every month and anti-HCV antibodies every six months are recommended (49). If ALT level is increasing, immunological testing for detecting HCV infection is recommended, otherwise it is unnecessary (49).

When a new case of HCV infection, seroconversion, is detected among the elderly patients of a dialysis center, an epidemiological inquiry should be performed, which should evaluate the possibility that the viral infection might have been acquired within the hemodialysis center or outside it, in other circumstances. An internal audit of the clinical practice should be performed regarding the correct application of the rules for preventing infection transmission and for proper hand hygiene, as well as the adequate employment of protective gloves. Furthermore, the viral status of the other patients of the dialysis center exposed to the infection risk should be assessed. For a good management, great importance should be attached to spotting and correcting any error in the control of infection prevention (48).

Although HCV infection remains present in hemodialysis centers, a decrease in transmission between patients has been observed in recent years (9). Properly performing blood donor screening as well as reducing the need for transfusions in CKD patients (secondary to ESA treatment) are the most important elements that contributed to the slight decrease in the transmission rate of HCV virus in hemodialysis centers (50). Currently, an important cause of transmission of HCV infection within the hemodialysis center remains the failure to comply with the transmission prevention measures described in the specialized guides (11,17,51-54). In this sense, currently, within the hemodialysis centers the most frequently incriminated methods for transmitting HCV infection are represented by the inappropriate use of the medical equipment, the non-observance of the regular hygiene or of the administration of the parenteral treatment (55,56).

The above is supported by the data provided by the CDC in the period 2008-2015. According to reports, during this period, the incorrect application of the protocols to prevent the transmission of infection within the hemodialysis center was the main cause of HCV outbreaks (57).

Thus, in order to prevent the transmission of HCV infection, it is necessary to intensify the training actions of the medical personnel (58).

The importance of this decision is emphasized by the following: The persistence period of HCV on various surfaces (at room temperature) is over 16 h (11,17,29,38-42) and the incorrect manipulation of products that get into contact with the contaminated blood of patients can easily result in the dissemination of blood-borne viral infections (11).

The association of HCV infection with an increased mortality in the chronic hemodialysis patients emphasizes the great importance of prevention in the disease transmission within hemodialysis center. The application of the measures recommended by the international guidelines regarding the prevention of infection transmission within hemodialysis centers is of great importance. However, further studies are necessary for evaluating the way these universal rules should be applied to the geographical location of each hemodialysis center, with the aim of elaborating individualized good practice protocols.