Non-immunological complications following kidney transplantation

Kidney transplantation (KT) is the most effective way to decrease the high morbidity and mortality of patients with end-stage renal disease. However, KT does not completely reverse the damage done by years of decreased kidney function and dialysis. Furthermore, new offending agents (in particular, immunosuppression) added in the post-transplant period increase the risk of complications. Cardiovascular (CV) disease, the leading cause of death in KT recipients, warrants pre-transplant screening based on risk factors. Nevertheless, the screening methods currently used have many shortcomings and a perfect screening modality does not exist. Risk factor modification in the pre- and post-transplant periods is of paramount importance to decrease the rate of CV complications post-transplant, either by lifestyle modification (for example, diet, exercise, and smoking cessation) or by pharmacological means (for example, statins, anti-hyperglycemics, and so on). Post-transplantation diabetes mellitus (PTDM) is a major contributor to mortality in this patient population. Although tacrolimus is a major contributor to PTDM development, changes in immunosuppression are limited by the higher risk of rejection with other agents. Immunosuppression has also been implicated in higher risk of malignancy; therefore, proper cancer screening is needed. Cancer immunotherapy is drastically changing the way certain types of cancer are treated in the general population; however, its use post-transplant is limited by the risk of allograft rejection. As expected, higher risk of infections is also encountered in transplant recipients. When caring for KT recipients, special attention is needed in screening methods, preventive measures, and treatment of infection with BK virus and cytomegalovirus. Hepatitis C virus infection is common in transplant candidates and in the deceased donor pool; however, newly developed direct-acting antivirals have been proven safe and effective in the pre- and post-transplant periods. The most important and recent developments on complications following KT are reviewed in this article.


Introduction
End-stage renal disease (ESRD) is one of the leading causes of premature mortality, and the death rate for patients on dialysis is 166 per 1,000 patient-years 1 . Kidney transplant is the best treatment of ESRD and decreases the mortality rate to 29 per 1,000 patient-years 1 . Despite this, kidney transplant recipients still experience a high incidence of complications in the posttransplant period. On one hand, the pre-transplant period, in which the patients had a very low glomerular filtration rate (GFR) and were on renal replacement therapy, inherently confers a high risk of complications which are not completely reversed by a kidney transplant. On the other hand, new factors are added in the post-transplant period, most notably immunosuppressive medications and their side effects. Therefore, the post-transplant period is associated with a wide range of complications, including cardiovascular (CV), metabolic, oncologic, infectious, immunological, surgical, osseous, and hematologic complications. This review will focus on CV, metabolic, oncologic, and infectious complications with an emphasis on areas with important developments in recent years. We chose to review these particular complications because of their frequency and associated mortality in kidney transplant recipients ( Table 1). Much of the management and screening of post-kidney transplant complications occurs while the patients are being evaluated for kidney transplant candidacy in the pre-transplant period, which will be reviewed here alongside specific post-transplant management.

Cardiovascular disease
Chronic kidney disease (CKD) is an independent risk factor for atherosclerotic coronary artery disease (CAD), and CAD incidence and severity increase as the GFR declines 2,3 . By the time patients reach ESRD, the prevalence of coronary artery stenosis ranges from 37% to 58% in asymptomatic patients 4 .
Although kidney transplant is the most effective way to decrease the risk of CV events, CV death still accounts for 30% of overall mortality, the most common cause of death in the post-transplant period 5 . The cumulative incidence of myocardial infarction in the post-transplant period is 4.2% to 11.1% at 3 years 6,7 . Therefore, two strategies are commonly used to decrease the incidence of CV disease in post-transplant patients: (1) pre-transplant screening with subsequent treatment and exclusion of very high-risk patients from listing and (2) risk factor modifications in the pre-and post-transplant period.
The most important CV risk factors in the ESRD population include diabetes mellitus (DM), prior CV disease (including stroke and peripheral arterial disease), dialysis vintage of more than 1 year, left ventricular hypertrophy, age greater than 60 years, smoking, hypertension, and dyslipidemia 5 . Many of these risk factors persist in the post-transplant period but others can develop de novo, including post-transplantation diabetes mellitus (PTDM) (previously known as new-onset diabetes after transplantation), drug-induced hypertension, drug-induced dyslipidemia, proteinuria, and chronic inflammation 8,9 . Nontraditional CV risk factors in the post-transplant period include intrarenal resistive index (RI) greater than 0.80, which is associated with higher risk of death 10 . Interestingly, the RI during protocol biopsies correlates more with recipients' factors (for example, age and central hemodynamic factors) than with graft or histologic factors 10 . Hypotension in the pre-transplant period might also be a risk factor for adverse outcomes in the posttransplant period, evidenced by recent studies associating the use of midodrine in the pre-transplant period with graft failure, death, and major adverse cardiovascular events (MACE) post-transplant 11,12 .
Identification and optimization of modifiable risk factors are of utmost importance for prevention of CV events post-transplant. Lifestyle modifications, including exercise, smoking cessation, and maintenance of a healthy weight, are always recommended. Treatment of all post-transplant patients with a statin is suggested by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines on lipid management (grade 2A) 13 based on the ALERT (Assessment of Lescol in Renal Transplantation) trial, which showed that fluvastatin decreases the risk of MACE in kidney transplant patients 14,15 . Treatment with reninangiotensin-aldosterone system blockade to decrease proteinuria and hence to decrease CV risk has not proven to be as effective as in the general population 20-22 , but larger prospective studies are needed before reaching a definitive conclusion.
The ideal screening strategy is unknown and differs across transplant centers. Current clinical guidelines are based mostly on expert opinion with a low level of evidence, but the general recommendation is the use of a risk-stratified approach in which non-invasive techniques are used first, and coronary angiography is reserved for high-risk patients or when the non-invasive tests are abnormal 5,23-26 . However, clinicians need to be aware that the pre-transplant CV evaluation should not be the same as for any other non-cardiac surgery, particularly because of the high risk of severe allograft dysfunction (in 6% to 33% of patients) and allograft loss (in 3% to 12% of patients) if cardiac surgery is required in the post-transplant period 27-30 . Therefore, it is very important to note that the goal of the screening strategy is to decrease the CV events and mortality not only in the perioperative period but also in the long term 5 .
The risk-stratified approach has proven beneficial for low-risk patients in whom the event rate is very low and invasive tests are therefore unnecessary 4 . This strategy is more controversial for intermediate-and high-risk patients for several reasons. First, the accuracy of stress tests compared with that of coronary angiography is limited (  32 . These results might have also been affected by referral bias given that many of the patients who underwent coronary angiography had an abnormal non-invasive test previously. When revascularization is indicated, this should occur prior to transplantation 5 . However, clinicians need to take into account the need for antiplatelet or anticoagulation treatment after revascularization, which could delay or postpone transplantation. Therefore, a perfect screening test for CV disease in kidney transplant candidates does not exist and all of the existing strategies have deficiencies. Newer CV tests, including the coronary artery calcium score (CACS) and coronary computed tomography (CT), are now being studied in the ESRD population. The correlation between CACS and angiographic CAD in the CKD/ESRD population is uncertain [33][34][35][36] given that high calcium scores may reflect medial instead of intimal vascular calcifications (Table 2). Nevertheless, CACS has been studied prospectively in two trials in kidney transplant candidates with conflicting results regarding the ability of CACS to predict MACE and mortality in comparison with MPS 37,38 . Therefore, at this time, the CACS cannot be recommended as a first-line strategy for CV disease screening pre-kidney transplant.
Coronary CT has good correlation with angiographic coronary disease 34,39 , and an abnormal coronary CT is an independent risk factor for adverse CV outcomes in kidney transplant candidates 38,40 . These results are from relatively small studies and require validation in larger trials with a more diverse population before the widespread use of coronary CT can be recommended as a CV disease screening method in renal transplant candidates. Furthermore, there is a safety concern of performing coronary CT in patients with residual kidney function given the exposure to iodinated contrast media. Notably, coronary CT is solely a diagnostic modality and in the event of a positive test an invasive coronary angiography and angioplasty would be needed, requiring a second exposure to iodinated contrast media. Another concern regarding most tests used for CV disease screening is the required radiation exposure in patients who will subsequently be at higher risk of cancer as a result of post-transplant immunosuppression.

Post-transplantation diabetes mellitus
Previously, transplant immunosuppressive regimens depended on high doses of corticosteroids, which led to an increased risk of DM after transplant (up to 50% of transplant recipients 41 ). Immunosuppression has evolved to rely more on calcineurin inhibitors (CNIs) than on corticosteroids. Despite this, the incidence of PTDM did not decline as expected, leading to the discovery of the diabetogenicity of CNIs, particularly tacrolimus 42 . However, since the early 2000s, the incidence of PTDM has declined 16 , probably due to decreased rates of rejection episodes and reduced exposure to corticosteroids and CNIs 42 . Changes in immunosuppression should be based on overall patient and allograft benefit rather than on the risk of PTDM development alone 46 . Although tacrolimus has a higher risk of PTDM compared with cyclosporine A 42,68 , the former is generally preferred because of the lower risk of rejection and higher graft survival 69 . The benefit of early corticosteroid withdrawal has been controversial; the largest randomized trial found no difference in PTDM development at 5 years post-transplant with corticosteroid maintenance versus early withdrawal 70 . This contrasts with the findings of an earlier meta-analysis that showed a reduced risk of PTDM with early steroid withdrawal but also an increased risk of allograft rejection 71 . When steroid withdrawal is chosen, the PTDM incidence is similar if steroids are given for 10 days versus an intraoperative bolus only, but the incidence of rejection is higher in the second group 72 . Another potential strategy to decrease the risk of PTDM would be to use CNI-free regimens. Use of belatacept, a T-cell co-stimulation blocker, reduces the risk of PTDM by 39% compared with CNIs 73 . Although mammalian target of rapamycin (mTOR) inhibitors are associated with a better glycemic profile than tacrolimus, they result in a worse lipid profile and higher rejection risk 42 .
Treatment of DM in the post-transplant period includes lifestyle modification with particular attention to healthy weight maintenance as well as pharmacologic therapy. Owing to the lack of evidence derived from well-designed prospective clinical trials investigating differences in hard clinical end points such as mortality, allograft loss, and CV events in this population, the optimal pharmacologic agent in transplant recipients is not well established 42 . In the early post-transplant period, it is recommended to treat hyperglycemia with insulin since it is the safest and most effective agent in the context of high corticosteroid doses 46 . Furthermore, this approach appears to reduce the odds of developing PTDM by 73% in the first year post-transplant 74 . After corticosteroid doses are reduced, treatment with oral anti-hyperglycemic agents is recommended, but the choice of specific agent should be individualized. Because of a lack of evidence, the most recent consensus recommendations were unable to propose a hierarchy of anti-hyperglycemic agents for PTDM 46 . The most commonly used anti-hyperglycemic medications post-transplant include metformin, sulfonylureas (that is, glipizide and glimepiride), and meglitinides (that is, repaglinide). Newer medications such as DPP-4 inhibitors (that is, sitagliptin, linagliptin, and vildagliptin) and GLP-1 agonists (exenatide and liraglutide) have been proposed for PTDM given their ability to counteract the effects of CNIs and corticosteroids by increasing glucose-dependent insulin secretion and inhibiting glucagon secretion 75 . In the general population, treatment with GLP-1 agonists decreases MACE 76,77 but this has not yet been confirmed in the kidney transplant population. Although no long-term randomized trials of these agents using clinical end points have been carried out for PTDM, studies have demonstrated that they are safe and effective in controlling hyperglycemia in post-transplant patients [78][79][80][81][82][83][84] . Finally, SGLT-2 inhibitors (that is, empagliflozin, canagliflozin, and dapagliflozin) have been shown to be effective in the general population in controlling hyperglycemia, reducing proteinuria, slowing kidney function decline, promoting weight loss, decreasing blood pressure, and reducing CV risk [85][86][87] . To date, only case reports and case series have reported the use of SGLT-2 inhibitors in the posttransplant period, and the biggest series of 25 patients has only been reported in abstract form 88-90 . These small series have shown that the effect of SGLT-2 inhibitors post-transplant is similar to the general population in terms of glucose control, weight loss, and decrease in blood pressure [88][89][90] (Table 3). Therefore, screening and preventative measures should be implemented in all transplant candidates and recipients. However, evidence to support a specific screening strategy is often lacking. A recent systematic review of clinical practice guidelines (CPGs) on cancer screening in solid organ transplant recipients highlights this point by demonstrating significant discrepancies across 13 CPGs (including eight CPGs specific to kidney transplant). Explanations for these differences include authors' interpretation of indirect data (that is, evidence of high incidence of a type of cancer but no evidence regarding the efficacy of the screening strategy) as well as lack of input from oncologists and public health and cancer screening experts 95 . Further research is needed to formulate evidence-based cancer screening guidelines for this high-risk population.
One of the most important risk factors for cancer development is tobacco use, but until recently there was only limited evidence regarding the benefits of smoking cessation. Opelz and Döhler 96 found that the incidence of several cancers, most prominently lung cancer, significantly decreases with smoking cessation before transplant; however, incidences remain higher than in never-smokers. In the same study, smoking cessation before transplant also decreased the risk of graft loss and death 96 . Hence, it is strongly recommended to encourage smoking cessation at the time of kidney transplant candidacy evaluation.
Immunosuppression is a prominent risk factor for cancer development, but whether specific immunosuppressive agents confer higher risk than others is an area of active study. Azathioprine increases the risk of squamous cell carcinoma but not other types of skin cancer 97,98 , whereas mycophenolate may be protective 98 . Conflicting results have been obtained in studies comparing tacrolimus with cyclosporine in regard to the risk of malignancy 99-104 . Belatacept confers increased risk of post-transplant lymphoproliferative disorder, particularly in EBV-seronegative patients [105][106][107] . In regard to induction therapy, alemtuzumab increases the risk of non-Hodgkin lymphoma, other virus-related cancers, and colorectal and thyroid cancer 99 whereas anti-lymphocyte globulin increases the risk of melanoma but surprisingly does not alter the risk of lymphomas 99,108 . Basiliximab did not increase the risk of cancers evaluated in this study 99 .
mTOR inhibitors (that is, sirolimus and everolimus) suppress growth and proliferation in malignant cells [109][110][111] . Hence, mTOR inhibitor-based regimens have been used de novo to prevent cancer development in transplant patients with high cancer risk and conversion to an mTOR inhibitor-based regimen is often considered if cancer is diagnosed. Whereas a 2014 metaanalysis showed a decreased risk of malignancy by 40% (driven mainly by the decreased risk of non-melanoma skin cancer) 112 , recent large studies have failed to show a difference in overall malignancy risk between patients on mTOR inhibitor-based immunosuppression and other regimens [113][114][115][116] . Some studies have not included non-melanoma skin cancer in their analysis, but most of the studies that did have found a decreased risk of non-melanoma skin cancer (particularly basal cell carcinoma) 112,114,[116][117][118][119] . Nonetheless, mTOR inhibitor-based immunosuppression regimens have been associated with increased risk of mortality 112,115 and post-transplant lymphoproliferative disorder 120,121 . Therefore, it is not recommended to change to mTOR inhibitor-based regimens after a cancer diagnosis. The only situation in which conversion to mTOR inhibitor-based regimen is recommended is in transplant patients diagnosed with KS 122 because of reports of complete regression of the KS lesion after conversion 123-125 .
Cancer immunotherapy is an emerging field requiring particular attention in kidney transplant recipients. Checkpoint inhibitors, which target the programmed cell death pathway (PD-1 and PD-L1) and the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), are effective in the treatment of several types of cancers, including melanoma, RCC, and non-small cell lung cancer 126,127 . However, case reports and series have reported a high risk of allograft rejection and loss with monoclonal antibodies against PD-1 but the incidence of this outcome is unknown 127-129 . Conversely, this outcome is seen less frequently with agents targeting CTLA-4 127 . A recent review found 17 reported solid organ transplant recipients (11 kidney, three liver, and three heart recipients) treated with these agents. One (16%) of six patients treated with the CTLA-4 inhibitor ipilimumab had allograft rejection, compared with 5 (62%) of 8 patients treated with PD-1 inhibitors, and 2 (66%) of 3 patients treated with CTLA-4 followed by PD-1 inhibitors 130 . A similar pattern was seen in the subset of kidney transplant recipients alone 130 . Further research is necessary to clarify the safety and effectiveness of checkpoint inhibitors in transplant recipients and for development of regimens that minimize the risk of allograft rejection, such as combining these agents with mTOR, BRAF, mitogen-activated protein kinase (MEK), and Bruton's tyrosine kinase (BTK) inhibitors 130 .

Infectious complications
Infectious complications are common during the post-transplant period and account for 13% of overall mortality in kidney transplant recipients 17 . The degree of immunosuppression and epidemiological exposures are the main determinants of the risk of infections. Transplant infectious disease experts typically divide the post-transplant period into three roughly different intervals 131 : (1) first month post-transplant, when infections are either a complication of the surgery/hospitalization or pre-existing in the donor or recipient; (2) one to six months post-transplant; this is the period when immunosuppression is often the highest and opportunistic infections (Pneumocystis jirovecii pneumonia, CMV or other herpes virus infections, mycobacterial infections, and so on) often happen, warranting prophylactic measures to prevent such infections; (3) after 6 to 12 months post-transplant, when immunosuppression is usually more stable and lower than in previous periods.
This timeline is obviously altered by heightened immunosuppression due to rejection episodes. During all of these periods, kidney transplant recipients are also at higher risk of "gardenvariety" infections such as community-acquired pneumonia, urinary tract infections, and so on.
In this article, we decided to focus on three particularly important subjects that either have changed dramatically in the last few years (that is, HCV) or warrant special attention in kidney transplant recipients (that is, CMV and BK virus), despite not being the most common infectious complications during the post-transplant period.

Hepatitis C virus
HCV infection is associated with higher incidences of CKD, faster progression to ESRD, and higher morbidity and mortality 132-134 . The prevalence of HCV in the ESRD population is significantly higher than in the general population, a finding which continues after transplantation 135 . HCV infection is associated with worse allograft outcomes (that is, allograft rejection, chronic allograft nephropathy and decreased graft survival), hepatic complications (that is, cirrhosis and hepatocellular carcinoma), PTDM, CV disease, de novo or recurrent glomerulonephritis, and overall worse patient survival [136][137][138][139][140][141] . Nevertheless, HCVinfected patients who receive a transplant have significantly lower morbidity and mortality than HCV-infected patients who remain on the waiting list 142-144 .
The availability of HCV-positive deceased donor kidneys has increased dramatically as a result of the opioid epidemic in the USA. Moreover, the waiting time for an HCV-positive kidney is much lower than for an HCV-negative kidney as these organs are currently not offered to HCV-negative transplant candidates 157,158,[165][166][167] . This leads to two important questions: (1) Should HCV-positive candidates be treated with DAAs before or after kidney transplantation? (2) Is it safe to transplant HCV-positive organs into HCV-negative recipients?
In terms of timing of HCV infection treatment, the most important factors to consider are DAA accessibility, the availability of HCV-positive organs, and the waiting time reduction in the area where the patient would be transplanted. If using HCV-infected donor kidneys results in a significant reduction in waiting time and DAAs are available, most patients would benefit from transplantation first followed by HCV treatment after transplantation. However, situations exist where treatment of HCV infection is indicated before transplant, including severe extrahepatic HCV manifestations such as mixed cryoglobulinemia syndrome, compensated cirrhosis with high risk of liver disease progression, and a living donor available only after 24 weeks (where there is no benefit of delaying the 12-week treatment and 12-week post-treatment monitoring for SVR) 135 .
Two trials evaluating the safety of transplanting HCV-positive organs to HCV-negative recipients have been published recently.
In the THINKER (Transplanting Hepatitis C kidneys Into Negative Kidney Recipients) trial 166,168 , 20 HCV-negative patients have been transplanted with HCV-infected kidneys followed by initiation of elbasvir/grazoprevir on post-transplant day 3. All recipients developed a positive HCV viral load post-transplant, but within 4 weeks of treatment the virus was undetectable, and 100% of patients achieved SVR at 12 weeks 166,168 . At 1 year of follow-up, allograft function, blood pressure, and proteinuria were excellent 155 . Another 10 HCV-negative recipients have been transplanted with HCV-positive kidneys in the EXPANDER-1 (Exploring Renal Transplants Using Hepatitis C Infected Donors for HCV-Negative Recipients) trial in which elbasvir/ grazoprevir was started immediately before transplantation. Only three patients had detectable HCV RNA early post-transplant, and 100% had negative HCV viral load at 12 weeks 169,170 . Both trials showed a good safety profile of elbasvir/grazoprevir early post-transplant and good early allograft outcomes 166,168-170 . Currently, this practice is recommended in the controlled setting of clinical trials only, but if the results of the THINKER and EXPANDER-1 trials are confirmed in larger studies, it might become a widespread practice that would expand the donor pool.

Cytomegalovirus
CMV remains a frequent infectious complication after kidney transplantation. Active CMV infection can lead to a viral syndrome (CMV syndrome) or tissue-invasive disease-including colitis, pneumonitis, nephritis, hepatitis, encephalitis, and retinitis-or both. Furthermore, CMV infection has "indirect effects", including increased risk of allograft failure 131,171 .
The most important risk factor is CMV serostatus in the donor and recipient, and the highest risk is in the CMV IgG-negative recipient transplanted with a CMV IgG-positive organ 172 . Another risk factor is level and type of immunosuppression; incidence is higher in patients induced with lymphocytedepleting agents (that is, thymoglobulin), and incidence is lower with mTOR inhibitor-based chronic immunosuppression regimens [173][174][175][176][177][178][179] .
CMV prevention strategies are commonly used post-transplant. The main approaches are universal prophylaxis or pre-emptive therapy. Universal prophylaxis entails administration of antiviral drugs (most commonly valganciclovir) to all patients or those at higher risk of CMV infection starting the first 10 days post-transplant and continuing for 3 to 6 months. Treatment duration is guided by the specific CMV status of donor and recipient. This approach is easier to implement and prevents early CMV infection; however, late CMV infection is more common with this approach, drug costs may be high, and patients often experience drug-induced adverse events, including leukopenia and hepatitis, among others 172 . Pre-emptive therapy involves CMV viral load monitoring at regular intervals (most often weekly), and therapy is started only when a specific viral load threshold is crossed. Because of the variability of the tests, no universal threshold to initiate therapy has been defined 180,181 . This approach eliminates the possibility of drug side effects and prevents late CMV infection better, but early CMV infection is more frequent. Moreover, this approach may be more difficult to implement and the costs of frequent monitoring might also be high 172 . A randomized trial comparing both approaches found no difference in the incidence of CMV disease 182  Drug resistance needs to be suspected when there is persistent CMV viremia or disease despite prolonged antiviral therapy (6 or more weeks of cumulative drug exposure or more than 2 weeks of ongoing full-dose therapy) 172 . Genotypic assays to detect mutations are used to test for resistance. In 90% of patients, mutation of the UL97 kinase gene appears first with varying degrees of resistance to ganciclovir but does not confer cidofovir or foscarnet resistance. UL54 mutations evolve later, conferring increased ganciclovir resistance and possibly cidofovir or foscarnet resistance or both. Depending on the mutation encountered, treatment with high doses of ganciclovir, foscarnet, or cidofovir could be indicated, but no controlled trials have defined the best intervention in these cases 172 .

BK virus
BK virus is a polyomavirus that is highly seroprevalent in humans but causes disease only in immunocompromised patients. Following kidney transplantation, BK virus causes tubulointerstitial nephritis in 1% to 10% of patients [185][186][187][188] . The most important risk factor for BK virus nephropathy development is the level of immunosuppression, but recent studies have demonstrated the importance of BK virus-specific T-cell functionality 189,190 and BK virus seroprevalence in donors and recipients, and risk is higher in those donor-positive/recipientnegative pairs 191,192 . Antibody-depleting induction therapy increases the risk of BK virus nephropathy, whereas mTOR inhibitor reduces the risk 193 .
Screening of BK virus nephritis relies on testing for viral replication in urine and blood. Viral replication in urine is tested with urine cytology looking for decoy cells or by polymerase chain reaction (PCR), whereas plasma or whole blood viral replication is confirmed by PCR. In general, the correlation with BK virus-associated nephropathy is higher for viremia (positive BK PCR in blood), lower for viruria (positive BK PCR in urine), and lowest for urine cytology (Table 4) 185,[194][195][196][197][198] . The KDIGO guidelines on kidney transplant recipients recommend urine or blood PCR monthly for the first 3 to 6 months posttransplant and then every 3 months until the end of the first post-transplant year 122 . However, other international consensus guidelines suggest continuing screening every 3 months until the end of the second year post-transplant and yearly thereafter 186,199 . Definitive diagnosis is made with histology on kidney allograft biopsy showing tubulointerstitial nephritis with cytopathic changes and positive immunohistochemistry for SV40 131 .
The cornerstone of therapy is reduction of immunosuppression 121 . However, the specific strategy of immunosuppression reduction is not well stablished and is mainly center-specific. A common practice is withdrawal of the antimetabolite drug (usually mycophenolate) and decrease of CNI dosing by 50%. Alternative approaches have been to stop tacrolimus and initiate either cyclosporine or an mTOR inhibitor. However, the evidence to support any of these approaches is low [200][201][202][203][204] . Some agents with antiviral properties have been suggested. Adding cidofovir or leflunomide does not increase graft survival 205 . Treatment with intravenous immunoglobulin (IVIG) is promising based on the fact that many formulations of IVIG have neutralizing BK antibodies 206 and several case series have described its efficacy 207,208 , but large randomized controlled trials are needed before its widespread use can be recommended. Although quinolones have been reported to have anti-BK properties, randomized trials have shown no benefit of adding levofloxacin 209,210 .

Conclusions
Kidney transplant recipients have a high risk of complications due to adverse events of potent immunosuppressive medications and their pre-and post-transplant complex medical history. It is important for the clinician taking care of these patients to be aware of the most common complications encountered in the post-transplant period and how to screen, diagnose, and treat Table 4. Non-invasive diagnostic tests for BK virus-associated nephropathy.

Grant information
The author(s) declared that no grants were involved in supporting this work.