CMV infection is the most important viral infection that can occur following SOT. CMV infection can directly and indirectly affect the kidney allograft. Direct effects include CMV syndrome (e.g., fever, fatigue, myalgia, and leucopenia) or tissue-invasive CMV diseases (e.g., pneumonitis, gastritis, duodenitis, or colitis). Regarding indirect effects, CMV infection can cause acute or chronic graft injuries, allograft rejection, poor graft survival, and acquisition of other opportunistic infections especially invasive fungal infections [24]. The risk factors for CMV infection are low lymphocyte count [25,26], low complement or natural killer cell count [27–29], IgG hypogammaglobulinemia [27,30,31], donor–recipient CMV serology mismatch, and the use of lymphocyte-depleting agents [32,33]. The incidence of CMV infection depends on the donor and recipient serology profiles. The incidence of CMV infection can reach up to 60% among patients with CMV IgG D+/R− [34]. The incidence of CMV infection varies from 5% to 30% for patients with CMV IgG R+ [35], but the incidence can be as high as 50% in patients who received T-cell depletion therapy [33,36,37].

Preventive strategies for CMV infection after SOTs are either preemptive or prophylaxis treatment. Patients with high risk (i.e., those who have D+/R− CMV IgG or who have received T-cell depletion for induction) should receive universal prophylaxis treatment, whereas patients with low to intermediate risk can undergo preemptive treatment. Kidney transplant recipients with CMV in a D+/R− situation should receive prophylaxis for 200 days; the IMPACT study showed that CMV disease occurred in 21.3% of the patients who received prophylaxis for 200 days and in 36.8% of the patients who received prophylaxis for 100 days [38]. The preemptive strategies require monitoring of CMV viral load at least once a week for three months after transplantation and, when the CMV viral load reaches the threshold, preemptive treatment should be started. However, the guidelines for management of CMV in SOT suggest that the dynamics of CMV viral load over time are more predicative of the disease than the absolute value [32]. These guidelines recommended using the World Health Organization international standard for surveillance and to report CMV viral load as IU/mL. The change of CMV viral load value should be significant if at least 0.5 log₁₀ IU/mL or at least three-fold changes were met. Table 1 compares the advantages and disadvantages between the two treatment approaches. Currently, both preventive measures are acceptable in R+ kidney recipients. However, several studies have demonstrated benefits of oral ganciclovir or valganciclovir prophylaxis over preemptive therapy in R+ patients including lower rates of CMV disease and impaired graft function [39–41]. Valacyclovir can be selected as an alternative option for CMV prophylaxis in kidney transplant recipients, since it showed comparable efficacy in CMV prevention to the preemptive approach in one study [42]. For preemptive CMV treatment, therapy should stop after the result is less than the lower limit of quantification, and the test should be repeated at one week thereafter [32]. Antiviral prophylaxis and preemptive approach are also preferred in transplant recipients who receive lymphocyte depleting agent for induction or treatment of rejection [24].

The drugs of choice for CMV syndrome and tissue-invasive CMV disease are valganciclovir or intravenous ganciclovir; the two drugs have the same efficacy and similar long-term outcomes [43]. However, intravenous ganciclovir is preferred as the initial treatment for patients with severe or life-threatening CMV disease, such as those with high viral load or those with questionable gastrointestinal absorption. The treatment should be continued for a minimum of two weeks or until the clinical symptoms have resolved and the virus has been eradicated; eradication of CMV is defined as a CMV viral load below the lower limit of quantification on one or two consecutive weekly samples. A secondary prophylaxis is not routinely recommended [32]. Foscarnet and cidofovir are considered as second and third line treatment which should be used only in documented UL97-mutant CMV strain due to their nephrotoxic property [24].

Epstein–Barr virus (EBV) is a gamma herpesvirus with a seroprevalence of more than 90% in adults. The clinical manifestation of EBV infection in SOT recipients varies from asymptomatic to uncomplicated infectious mononucleosis, hepatitis, pneumonitis, lung mass, lymphadenopathy, hepatosplenomegaly, central nervous systemic disease, gastrointestinal disease, and posttransplant lymphoproliferative disorder (PTLD). The incidence of PTLD varies by type of organ transplantation. Kidney transplantation has the lowest incidence, followed by pancreatic transplantation, liver transplantation, heart transplantation, lung transplantation, and small bowel transplantation, in that order [44–46]. Risk factors for developing PTLD include type of transplanted organ; EBV mismatch; and type of induction immunosuppressive therapy used such as antithymocyte globulin, muromonab-CD3, and belatacept [44,47].

The incidence of PTLD has a biphasic onset, which means that most cases of EBV-positive transplant recipients develop PTLD within the first year after transplantation, whereas EBV-negative transplant recipients develop PTLD five to 15 years after transplantation [45,48,49]. Intragraft PTLD occurred mainly in the first two years after transplantation. Cerebral PTLD occurred mainly between the second and seventh year after transplantation. The incidence of gastrointestinal tract PTLD was relatively low in the first five years and then increased dramatically at the sixth and seventh year posttransplantation, spreading to other locations of the body [50].

The diagnosis and categorization of PTLD depend on histopathology according to the World Health Organization 2017 classification. There are still no recommendations as to when EBV should be monitored for and what the cutoff values should be. The high-risk categories for EBV infection and PTLD were not clearly defined. PTLD can be treated by reducing the use of immunosuppressive drugs, surgical removal, radiotherapy, adoptive immunotherapy, or chemotherapy [51].

BKV is a nonenveloped, double-stranded DNA virus and a member of the Polyomaviridae family. BKV infection after transplantation can cause hemorrhagic cystitis, tubulointerstitial nephritis, ureteric stricture, BKV-associated nephropathy (BKVAN), and premature graft failure. The seroprevalence in adults was reported to be 40% to 100%. After BKV infection via the oral or respiratory tract, the BKV remains latent in renal tubular epithelial cells [52].

The risk factors for BKVAN include human leukocyte antigen (HLA)-mismatch, deceased donor, mismatched BKV-specific antibody of donor/recipient (D+/R−), older age of the recipient, retention of the ureteric stent, reception of antirejection treatment, tacrolimus–mycophenolic use, or retransplantation after graft loss due to BKVAN [52,53].

The incidence of BK viruria was reported to be 23% to 73%, that of BK viremia was 8% to 15%, and that of BK-VAN was 1% to 7%; the BKVAN rate is highest at three months to six months posttransplantation [53]. In Thailand, the incidence of BK viruria was 20%, that of BK viremia was 3.4% to 4%, and that of BKVAN was 6.4% to 8.4%. The significant risk factors for BKV infection were a mycophenolate dose greater than 1 g/day, receiving a kidney from a deceased donor, and/or CMV infection [54,55]. The median time to diagnosis of BKV infection was 6.8 to 10.9 months after transplantation [54,55], which matches findings from a previous report [52].

The recommendation for screening for BKV is by way of quantitative DNA virus testing of the urine every one month to three months during the first two years after transplantation and then annually until the fifth year posttransplantation. However, BK viruria is sensitive for detecting active BKV infection but not specific for nephropathy and has a positive predictive value of 29% to 67%. Detection of BKV DNA in plasma may represent a better indicator for nephropathy, especially when plasma BKV load is greater than 4 log₁₀ copies/mL or when there is impaired renal allograft function, which has a positive predictive value greater than 90%. The gold standard for diagnosing BKVAN is kidney histology, including tubulointerstitial nephritis with cytopathic changes and positive immunohistochemistry using antibodies generally targeting cross-reacting SV40 large T-antigen or BKV antigens, or in-situ hybridization for BKV nucleic acids [56].

The mainstay of treatment for BKVAN is to reduce immunosuppressive drugs. This can be done by withdrawing mycophenolate mofetil or tacrolimus, replacing tacrolimus with cyclosporine, or withdrawing CNIs. The efficacy of antiviral therapy as an adjuvant therapy to immunosuppression reduction is still controversial. Cidofovir is a nucleotide analogue of cytosine with an antiviral effect. It has been effectively used to treat BKVAN in kidney transplant recipients with a dose of 0.25 to 1.0 mg/ kg at one-week to three-week intervals [57,58]. However, there are also studies that have failed to show a benefit of cidofovir in the treatment of BKVAN [52,59]. Moreover, the nephrotoxicity of cidofovir is an important concern that can worsen allograft function. Large randomized clinical trials are required to demonstrate the true efficacy of cidofovir.

Leflunomide is another alternative treatment for BKV nephropathy. It is an anti-inflammatory drug that inhibits pyrimidine synthesis. In one study, leflunomide was administered at a loading dose of 100 mg/day for three days to five days followed by a maintenance dose of 20 mg to 60 mg daily, keeping the trough levels at 50 to 100 μg/mL [52]. An efficacy study of leflunomide in addition to immunosuppression reduction for the treatment of BK viremia and BKVAN showed that 42% to 71% of the patients cleared BKV viremia [60,61]; notably, only 54% of the patients used leflunomide at the therapeutic dose, and 60% of them required leflunomide at least 60 mg/day [60]. Leflunomide in combination with ciprofloxacin has been used in some centers and has shown possible benefits for virus reduction [62]. However, all of the publications of BKVAN treatment with leflunomide have been case series [63]. Without the results of controlled clinical studies to consider, utilization of leflunomide for treatment of BKVAN requires further evaluation.

Ciprofloxacin has antiviral activity against BKV by inhibiting DNA topoisomerase activity. Case reports and case series of successful ciprofloxacin uses for treatment of BKVAN in kidney transplantation have been reported [64,65]. However, levofloxacin, another quinolone, failed to demonstrate efficacy in the treatment of BK viremia in a multicenter, double-blinded, randomized placebo-controlled trial [66]. To date, the use of quinolones for treatment of BKVAN cannot be generally recommended due to the lack of strong evidence [67]. In Thailand, we observed the successful use of leflunomide with ciprofloxacin, along with decreasing immunosuppressive drug use in two BKVAN kidney transplant recipients. The kidney function of both patients improved, and their serum creatinine level decreased to baseline [68].

Intravenous Ig (IVIG) preparations were administered in doses ranging from 0.2 to 2.0 g/kg in conjunction with reduced immunosuppressive drugs [52]. A study of IVIG treatment was conducted in patients who did not respond to eight weeks of the adjusted immunosuppressive drugs and leflunomide and showed that 90% of the patients cleared viremia, and 96.7% of the patients had graft survival beyond 12 months [69]. A more recent retrospective cohort study of IVIG as an adjuvant therapy to the combination of immunosuppression reduction, leflunomide, ciprofloxacin, and cidofovir resulted in more effectively cleared viremia and BK immunohistochemistry from repeated allograft biopsy in comparison with the IVIG-nonreceiving group [70]. The combination of these treatments is interesting and might enhance the opportunity to improve allograft survival in patients with BKVAN.

HAV is a nonenveloped RNA virus from the Picornaviridae family that is transmitted via the fecal–oral route. This virus is considered to be the most common cause of viral hepatitis and the second most common infectious disease among travelers [71]. The incidence of HAV infection was estimated to be around 1.5 million cases per year, with the condition mostly occurring in developing countries including South Asia and Southeast Asia [72]. Clinical presentations are typical acute hepatitis that can range from mild jaundice to fulminant hepatitis; however, chronic hepatitis is rare [73,74]. Data on seroprevalence of HAV are scarce. In an endemic area, 73% of hemodialysis patients have positive HAV antibodies, and 90% of kidney transplant recipients with HCV coinfection have positive HAV antibodies [75,76]. According to the current recommendations, kidney transplant candidates and recipients who have chronic liver disease or risk factors for HAV should be tested for HAV IgG, and a vaccine should be offered to those with a negative result [77]. The HAV vaccine should be given in two doses at six months apart; seroconversion was found in only 24% to 27% of kidney transplant recipients [78,79]. Therefore, the HAV vaccine should be given prior to kidney transplantation. Moreover, the HAV can be transmitted through organ transplantation and reactivate after liver transplantation [80,81].

HBV is a DNA virus from the family Hepadnaviridae that primarily targets human hepatocytes, resulting in hepatitis. HBV can be transmitted sexually, mother-to-child, as well as via blood transfusion and organ transplantation [77]. After infection, the virion DNA is harbored in the nucleus of the hepatocyte, which can cause chronic infection and long-term complications such as cirrhosis or hepatocellular carcinoma [82]. Markers to detect HBV infection vary according to geographical area. In the Asia-Pacific region, the prevalence of hepatitis B surface antigen (HBsAg) positivity was between 1.3% and 14.6% in hemodialysis patients [83]. Reactivation of HBV after transplantation is an important concern and is found in up to 94% and 5% in recipients with positive HBsAg and antibody to hepatitis B core antigen (anti-HBc), respectively [84,85]. Therefore, an appropriate pretransplant evaluation for HBV infection is crucial. The HBV vaccine should be offered to patients with negative results for all serological markers for HBV infection. All recipients with chronic HBV infection should be evaluated for treatment prior to transplantation, and those who do not meet the treatment criteria should receive either tenofovir or entecavir after transplantation [86,87]. In recipients with isolated anti-HBc, prophylaxis is still the preferred strategy after transplantation [88].

HBV serology testing in donors is also an important issue because it can assist the physician with making a decision whether to use an organ or not. Organs from donors with isolated anti-HBc are acceptable for transplant; however, after treatment, the seroconversion was reported up to 10% in kidney recipients with antibody to hepatitis B surface antigen (anti-HBs) titer < 100 IU/L [77,89]. According to the current guidelines, antiviral prophylaxis is not required in recipients with anti-HBs titer above 10 IU/L; however, one-year lamivudine prophylaxis may be considered in recipients with negative anti-HBs [90]. Donors with positive HBsAg are considered to be contraindicated for organ utilization. The current data demonstrated that there is no evidence of donor-derived HBV infection; it has been shown that there is excellent graft survival in recipients with anti-HBs > 100 U/L who received an organ from a HBsAg-positive donor who did not receive any antiviral prophylaxis [7]. However, the consensus guidelines still recommend indefinite entecavir or tenofovir prophylaxis in all recipients regardless of immune status, and hepatitis B immune globulin (HBIG) should be considered in recipients with anti-HBs < 100 U/L [90].

HCV is an RNA virus from the Flaviviridae family. Similar to HBV, HCV can be transmitted via organ transplantation; blood exposure; sexual intercourse; and, more uncommonly, through the transplacenta. HCV can maintain its genome in the cytoplasm of hepatocytes and can cause chronic infection that can result in cirrhosis and hepatocellular carcinoma [91]. The seroprevalence of HCV ranges between 5% and 60% among hemodialysis patients, differing according to geographic location [92]. Data have clearly shown that HCV-positive recipients who undergo kidney transplantation have better survival rates than do patients on the waiting list. However, these populations still have a lower rate of graft survival compared with HCV-negative transplant recipients [93,94]. Initial screening for anti-HCV should be performed in all transplant candidates. If the patient has a positive anti-HCV result, then HCV viral load should be done. Candidates with documented chronic HCV infection should be handled on a case-by-case basis. The HCV genotype and hepatic fibrosis should be assessed to determine whether the patient should undergo the transplantation procedure. Patients with mild to moderate liver disease (F0–F2) do not require treatment before listing, whereas those with bridging fibrosis (F3) and compensated cirrhosis (F4) should be treated and achieve a sustained virological response (SVR) prior to listing [77,95].

In the past, the treatment options for HCV in transplant recipients were limited because pegylated-interferon-based regimens increased the rate of acute allograft rejection. Currently, DAAs target the NS5B polymerase, NS5A protein, and NS3/4A protease; these drugs have been approved as the standard treatment for chronic HCV infection. DAA-based regimens yield a greater than 90% SVR at 12 weeks, especially in naïve patients [96]. Several reports using DAA-based regimens in kidney transplant recipients demonstrated similar SVR rates; furthermore, there were no significant adverse drug reactions or instances of graft rejection when these drugs were used in kidney transplant recipients [97,98]. However, there are significant drug–drug interactions between simeprevir and cyclosporine as well as the combination of parita-previr/ritonavir/ombitasvir/dasabuvir and cyclosporine or tacrolimus. Therefore, the doses of immunosuppressive drugs should be adjusted, and their levels should be closely monitored [99]. The utilization of organs from HCV-positive donors is currently an interesting issue because there is a limited donor pool and high mortality rate among those patients on the waiting list. For nonhepatic transplantation, organs from HCV-positive donors should be considered for HCV-positive recipients, while transplantation to HCV-negative recipients remains contraindicated [77]. Nevertheless, there was an open-label pilot study conducted using organs from HCV type 1 viremic donors for HCV-negative recipients followed by DAA therapy after transplantation. After six months of follow-up, all patients achieved SVR with good graft function. This result may suggest efficacy and safety in utilizing HCV-positive organs for HCV-negative recipients, but more data are needed [100].

Hepatitis D virus (HDV) is a small RNA virus that requires the presence of HBsAg to complete the process to release virion [101]. Along with HBV, HDV can be transmitted via illicit drug use, blood transfusions, and sexual intercourse. HBV–HDV coinfection is common in specific areas such as the Pacific island. Testing for HDV infection is not recommended during routine screening, unless there is a high level of suspicion [77]. Data of HDV after transplantation were mostly sourced from cases of liver transplantation. None of the cases with HBV–HDV coinfection developed recurrent HDV viremia after clearance of HBsAg posttransplantation. Despite the lack of effective medication against HDV, the adequate control of HBV seems to be an appropriate practice in managing HDV infection [102].

Hepatitis E virus (HEV) is an RNA virus from the family Hepeviridae that transmits via the fecal–oral route similarly to HAV. HEV is known to cause self-limiting hepatitis, but severe fulminant disease can occur in individuals with chronic hepatitis or pregnant women. The prevalence of HEV was found to be higher in developing countries. The seroprevalence of anti-HEV IgG was 2.6%, 3.9%, and 10.4% in liver transplant recipients from Japan, the Netherlands, and France, respectively, while positive anti-HEV IgG was found up to 14.5% and 26% among kidney transplant recipients in France and Thailand. Since there is a low prevalence of HEV, routine screening is not recommended in transplant candidates [103–105]. One study from France reported a 6.5% prevalence of acute HEV in organ transplant recipients, with more than half of the recipients progressing to chronic hepatitis; the diagnosis was done by polymerase chain reaction using serum and stool specimens [105]. Chronic HEV infection in both hepatic and nonhepatic transplant recipients can have long-term complications such as liver fibrosis and HEV-associated glomerulonephritis [106–108]. A reduction in immunosuppressive agent use was associated with viral clearance in more than 30% of the patients and should be considered as a main therapy in managing chronic HEV infection [109]. Pegylated IFN-α contains some antiviral activities against HEV but also carries the risk of allograft rejection [110]. A three-month course of ribavirin was used for the treatment of chronic HEV (genotype 3) and yielded 95% viral clearance with 78% SVR at six months in one retrospective, multicentered study [111]. While no antiviral agent is currently recommended in the standard guidelines, treatment with ribavirin seems to be promising; however, additional studies are needed to confirm the efficacy and safety of ribavirin in treating HEV.