Infection and chronic allograft dysfunction

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http://www.kidney-international.org & 2010 International Society of Nephrology

Infection and chronic allograft dysfunction Peter J. Dupont1, Oriol Manuel2 and Manuel Pascual2 1

Department of Nephrology and Transplantation, Royal Free Hospital, London, UK and 2Transplantation Center, University of Lausanne, Lausanne, Switzerland

With the advent of more potent immunosuppressive regimens, the incidence of acute rejection following renal transplantation has declined sharply in recent years. In spite of this, long-term graft outcomes remain suboptimal because of relentless attrition by cumulated insults to the allograft. As acute rejection rates have declined, other causes of graft injury and loss have recently emerged. Among these, infectious diseases remain a persistent threat and can be associated with allograft dysfunction. This group includes nephropathy due to polyoma (BK) virus infection, cytomegalovirus disease, and bacterial infection (the latter most commonly arising from the urinary tract). Rarer infectious causes of chronic allograft dysfunction include cryoglobulinemia associated with hepatitis C, Epstein–Barr virus-associated posttransplant lymphoproliferative disease, and direct cytotoxicity from adenoviral infection or parvovirus B19. Kidney International (2010) 78 (Suppl 119), S47–S53; doi:10.1038/ki.2010.423 KEYWORDS: BK virus; chronic allograft dysfunction; cytomegalovirus; infection; urinary tract infection TO CITE THIS ARTICLE: Dupont PJ, Manuel O, Pascual M. Infection and chronic allograft dysfunction. Kidney Int 2010; 78 (Suppl 119): S47–S53.

Correspondence: Peter J. Dupont, Department of Renal Medicine, Royal Free Hospital, Pond Street, London NW3 2QG, UK. E-mail: [email protected] Kidney International (2010) 78 (Suppl 119), S47–S53

In recent years, the incidence of acute rejection following renal transplantation has declined sharply because of the introduction of a variety of potent new immunosuppressive drugs.1,2 In spite of this, long-term graft outcomes have changed little.3,4 As acute rejection rates have declined, the relative contribution of other causes of graft injury has become more important. Infectious diseases continue to affect graft and patient survival and contribute to the development of chronic allograft dysfunction. This group of diseases includes nephropathy due to polyoma (BK) virus infection, direct and indirect effects of cytomegalovirus (CMV) infection, and bacterial infections (the latter most commonly arising from the urinary tract). Rarer infectious causes of graft dysfunction include cryoglobulinemia associated with hepatitis C, Epstein–Barr virus (EBV)-associated posttransplant lymphoproliferative disease (PTLD), and direct cytotoxicity from adenoviral infection or parvovirus B19. In this review, we will focus principally on the more common viral and bacterial infections that can be associated with chronic allograft dysfunction and loss. BK VIRUS

BK virus-associated nephropathy (BKVAN) was first described by Gardner et al.5 in 1971 but only emerged as a significant clinical problem in the mid-1990s with the advent of more potent immunosuppressive regimens.6–9 Although early reports suggested a link with tacrolimus- and mycophenolate-based regimens,10,11 it seems likely that the risk of BK nephropathy relates to the total burden of immunosuppression rather than to any specific drug.12,13 Prospective screening studies suggest that 50% or more of patients develop BK viruria after transplantation, with a peak incidence in the first 3–12 months.11,14,15 However, only 1–5% of viruric patients go on to develop nephropathy.16,17 When BKVAN occurs, reported rates of graft loss have ranged from 10 to 80% (refs 8,9,16–19). The pathogenesis of BKVAN depends on a variety of host and viral factors, such as impairment of cellular and humoral response and presence of renal allograft injury.20,21 For example, the strength of the CD8 þ and CD4 þ T-cell immune response to BK virus VP1 and large T antigen has been correlated with the degree of BK viral load and the persistence of viral replication.22 In addition, BK seronegative recipients seem to be more at risk for the development of BKVAN than BK seropositive recipients, although a S47

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preexistent humoral response does not protect from nephropathy.23,24 As BKVAN is almost exclusively observed after kidney transplantation but not with other organ transplants,25 some authors have hypothesized that the injury of the renal allograft may have an important role in the pathogenesis of BKVAN.26 The association found between human lymphocyte antigen mismatching and BKVAN supports this hypothesis.27 Screening for BK nephropathy is sometimes performed by urine cytology to detect shedding of so-called ‘decoy cells’ (virally loaded epithelial cells). This technique has a poor positive predictive value, but it is useful to rule out BK nephropathy with a negative predictive value of 97–100% (refs 28,29). More expensive screening methods based on detection of BK viral DNA in blood or urine by polymerase chain reaction (PCR) have also been proposed.11,30 These have improved the positive predictive value for the presence of nephropathy, compared with urine cytology, but allograft biopsy with immunostaining for the SV40 large T antigen remains the ‘gold standard’ for diagnosis (Figure 1). Management of established BK nephropathy remains unsatisfactory because of the absence of effective specific antiviral therapies. Reduction of overall immunosuppression is, therefore, still the mainstay of treatment. In spite of this, graft loss occurs, although rates have fallen to o10% in some recently reported series.14,31 For refractory cases, there are reports that cidofovir therapy may be effective;32–34 however, evidence from prospective randomized controlled trials is still awaited. A recent systematic review showed a suboptimal efficacy of cidofovir for the treatment of BKVAN.35 Leflunomide has also been tried, usually in combination with a reduction in immunosuppression, with variable results.36,37 In the near future, early diagnosis by protocol-driven screening is likely to remain the key to the prevention of nephropathy. One proposed algorithm38 is 3-monthly screening for the first 2 years (by urine cytology or by PCR) and then annual screening thereafter. In cases in which urine cytology is positive, this should be followed up with PCR of blood for viral DNA, and if the latter is positive, a biopsy performed to confirm the diagnosis. Alternatively, a direct viral screening with serial blood PCR during the first year after transplant may be more cost-effective. A generally accepted threshold predictive for BKVAN is 4104 DNA copies/ml in blood.39 Quantitative blood PCR is also useful for monitoring subsequent response to therapy. CMV

The extent of the contribution of CMV infection to chronic allograft dysfunction remains controversial. Direct cytopathic effects of CMV on the renal allograft are well described40–42 but relatively uncommon in clinical practice. Histological findings include CMV inclusions in glomerular endothelial cells, peritubular capillaries, and tubular epithelial cells. An immunotactoid glomerulopathy43 and a monocytic interstitial nephritis44 in the context of acute CMV infection have also been described. Other effects such as CMV-associated S48

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Figure 1 | BK virus in the nuclei of tubular cells in a renal allograft, shown by immunoperoxidase staining. Courtesy of Alexander J Howie, University College London.

Figure 2 | Cytomegalovirus (arrow) in a glomerular endocapillary nucleus, shown by immunoperoxidase staining. Courtesy of Alexander J Howie, University College London.

glomerulopathy may in fact be an indirect consequence of the interaction between CMV and the host immune system. CMV infection has been shown to upregulate class I and II major histocompatibility complex molecules on T lymphocytes, and on renal parenchymal cells. This latter effect is likely to be a cytokine-mediated phenomenon because of upregulation of proinflammatory cytokines such as interferon-g (Figure 2). A further observation is that the immediate early gene product of CMV shares a sequence homology with human lymphocyte antigen DR.45 Whether such ‘molecular mimicry’ has a role in allorecognition by recipient T lymphocytes in clinical practice remains unknown. CMV infection also blocks p53 (an important cell cycle regulatory protein), which may inhibit apoptosis and promote graft vasculopathy.46 Other potential indirect effects of CMV include upregulation of antiendothelial antibodies (contributing Kidney International (2010) 78 (Suppl 119), S47–S53

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to graft vascular injury)47 and upregulation of adhesion molecules (for example, intercellular adhesion molecule-1),48 leading to enhanced adhesion of host leukocytes to graft endothelium, thereby promoting allograft injury and/or rejection. These indirect effects of CMV are thought to affect graft survival principally through an increased risk of acute rejection. This could represent a two-way relationship. CMV infection may predispose to acute rejection by means of the mechanisms outlined above and, conversely, the enhanced immunosuppression deployed to treat acute rejection may predispose to CMV infection or reactivation. Comparative studies of antiviral prophylaxis elegantly demonstrate that prevention of CMV infection may reduce acute rejection rates, albeit mainly in D þ /R seropairings. Ten years ago, Lowance et al.49 reported lower rates of acute rejection at 6 months in a group receiving valaciclovir prophylaxis compared with placebo (26 vs 52%; P ¼ 0.001). This benefit was only seen for seronegative recipients. Data from Opelz et al. and the Collaborative Transplant Study50 also demonstrated improved graft survival among patients taking antiviral prophylaxis (at 3 years, graft survival was 79.4% with prophylaxis vs 73.5% without prophylaxis; relative ratio 0.80, Po0.0001) but again the benefit was confined to the D þ /R group. These findings are not universal, however, as an earlier meta-analysis found no significant impact of prophylaxis on acute rejection rates or graft survival.51,52 Although the combination of CMV infection and acute rejection has an adverse effect on graft survival, the more difficult question of whether CMV infection on its own contributes to graft failure, in the absence of acute rejection, remains unclear. There is some evidence, mainly from animal models, suggesting a direct role for CMV in mediating chronic allograft dysfunction. CMV infection has been shown to have both proinflammatory and profibrotic effects. In rodents, CMV upregulates transforming growth factor-b, platelet-derived growth factor (which stimulates smooth muscle proliferation and fibroblast activity), and connective tissue growth factor.48,53–55 Clinical studies have demonstrated similar effects in man.48 CMV infection is also known to induce macrophage scavenger receptors and phenotypic changes in vascular smooth muscle cells, which have been shown to contribute to vasculopathy in cardiac allografts.56 These observations might suggest that prevention of CMV infection by universal antiviral prophylaxis might be a superior strategy compared with preemptive treatment of infection, particularly for the D þ /R seropairings. To date, however, there has been no consistent evidence that one strategy is superior to the other.57 There are also concerns that routine antiviral prophylaxis might promote resistance in some cases and impair subsequent development of host immunity to CMV. Recently, a German trial compared 3 months of prophylaxis with oral ganciclovir to a preemptive strategy consisting of monitoring CMV viremia (biweekly by PCR), followed by treatment of viremia with intravenous ganciclovir.58 The main end point was the incidence of graft Kidney International (2010) 78 (Suppl 119), S47–S53

loss at 4 years, which was significantly higher in the preemptive group (21.7 vs 7.8%, respectively; P ¼ 0.04). Interestingly, the main benefit from prophylaxis was observed in seropositive recipients (R þ ), a relatively lower risk group for CMV infection. With the increasing use of universal antiviral prophylaxis in most transplant centers, a new concern has emerged, namely, the development of CMV disease after discontinuation of antiviral prophylaxis, that is, the so-called late-onset CMV disease (reviewed by Meylan and Manuel59 and Legendre and Pascual60). Late-onset CMV disease can be observed in up to 35% of D þ /R recipients. It is still debated whether late-onset CMV disease has indirect consequences similar to classic, early-onset CMV disease, and whether it can participate in the development of acute rejection and allograft loss.61,62,63 Although some studies associated late-onset CMV disease with a higher mortality, other studies did not confirm these observations. URINARY TRACT INFECTION

Urinary tract infection (UTI) is a common complication following renal transplantation, with a reported incidence ranging from 6 to 83% (refs 64–69). In the first 3 months after transplantation, infection often presents as overt pyelonephritis and is associated with relatively high rates of bacteremia.70,71 Later episodes are often subclinical, manifesting as asymptomatic bacteriuria detected only by routine urine screening.64,66 Graft pyelonephritis is well recognized to cause acute graft dysfunction but the longer-term impact is less clear.72 One of the largest retrospective series suggests that the overall impact on graft survival is not significant, but subgroup analysis of those with infections occurring in the first 3 months after transplantation suggests a long-term adverse effect.73 Interestingly, although it is tempting to speculate that graft pyelonephritis might trigger immunological ‘danger signals’ within the allograft, the effect on graft survival in this study was not mediated by an increased rate of acute rejection. The significance of UTIs occurring in the late posttransplant period (beyond the first 6 months) is also an area of controversy. The conventional wisdom, extrapolated from pediatric studies on children with vesico-ureteric reflux, is that scarring of kidneys as a consequence of UTI is rare beyond 5 years of age.74 Hence, adult kidneys (including renal allografts) have been considered largely unsusceptible to scarring.74,75 Recurrent UTIs have thus not been generally accepted as a cause of late graft dysfunction,64,65,70,76–78 although this assertion seems to be based on only a handful of small studies.64,79–81 A review of US registry data by Abbott and colleagues82 challenged this view and suggested that late UTIs are not benign but they may be associated with an increased risk of death and graft loss. Causality was not established in this registry-based study as patient deaths were predominantly from cardiovascular rather than infective causes and, although rates of graft loss were certainly higher in those S49

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with late UTIs, rates of graft loss specifically due to infection were not significantly different. This raised the question as to whether this was a direct causative effect or whether UTIs were simply a marker for serious underlying disease. However, other studies have reported a similar association that adds weight to the arguments in favor of a direct effect. Muller et al.83 found that adult patients with a history of recurrent UTIs were more likely to develop chronic allograft nephropathy. This association reached statistical significance beyond the first 2 years after transplantation (in year 4, patients with chronic allograft nephropathy had a significantly higher incidence of UTI than those without chronic allograft nephropathy (1.25 vs 0.6 UTI/year; Po0.05). In the pediatric transplant population, Dharnidharka et al.84 reported increased rates of graft loss in patients with a history of early UTI (o6 months) with an adjusted hazard ratio for graft loss of 5.47. For late UTIs (46 months), the adjusted hazard ratio was 2.09, although this figure did not reach statistical significance. With regard to potential mechanisms whereby UTI might directly cause graft injury, Dupont et al.85 showed an increased prevalence of allograft scarring (demonstrated by DMSA SPECT scan) in patients with a history of recurrent UTIs in the late posttransplant period, compared with those with no such history. Patients with vesico-ureteric reflux had the highest rates of scarring, but vesico-ureteric reflux was not a prerequisite for the development of scars. In all, 50% of those with scars had had an episode of symptomatic graft pyelonephritis at some point in the past, but scars were also seen in those without such a history. Regarding the prevention of UTI, patients usually receive antimicrobial prophylaxis with cotrimoxazole during the first 6 months after transplant, which has been proven to be an effective strategy to reduce the number of UTIs in the early posttransplant setting.86 In addition, most centers routinely screen for asymptomatic bacteriuria, although it is not yet clear whether asymptomatic bacteriuria should be treated, especially after the first 3–6 months after transplant.87 Prospective trials to evaluate the influence of untreated asymptomatic bacteriuria in kidney allograft recipients are awaited. No consensus exists as to the best preventive strategy in patients with recurrent UTI. A consultation with the urologist may be needed in case of vesico-ureteric reflux or other anatomical abnormality. Long-term prophylaxis can be proposed to the patient, but the benefits need to be weighed against the risk of promoting the emergence of resistant pathogens. EPSTEIN–BARR VIRUS

The uncontrolled proliferation of EBV after organ transplantation may result in the occurrence of a variety of PTLDs, ranging from a mononucleosis-like syndrome with lymphoid hyperplasia to aggressive forms of lymphoma.88 Risk factors associated with PTLD include the EBV donor/recipient serostatus (with the donor positive/recipient negative (D þ / R) combination at highest risk), the net state of S50

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immunosuppression, and probably coinfection with other viruses (particularly CMV).89,90 PTLD incidence rates in kidney transplant recipients are among the lowest of all organ transplant recipients (B1%).89 Although PTLD causes significant morbidity and mortality, its association with kidney dysfunction and graft loss is less established. In a retrospective analysis of 1474 kidney transplant recipients, 10 of 14 cases of PTLD were localized near (or involved) the allograft.91 All 10 patients presented with some degree of impaired kidney function secondary to vessel stenosis or hydronephrosis. Overall, 70% of these patients required nephrectomy because of acute rejection after reduction of immunosuppression. Other studies have shown similar outcomes,92 indicating that EBV-associated PTLD can be a rare cause of allograft dysfunction. HEPATITIS C

Kidney allograft dysfunction secondary to chronic hepatitis C virus (HCV) infection has occasionally been described, although the exact incidence is not well characterized.93,94 The main cause of HCV-associated allograft nephropathy is membrano-proliferative glomerulonephritis associated with mixed cryoglobulinemia.95 Cases of focal segmental glomerulonephritis,96 acute transplant glomerulopathy,97 and renal thrombotic microangiopathy associated with anticardiolipin antibodies98 have also been described in this setting. In addition, HCV infection is an established risk factor for the development of diabetes mellitus after transplantation, which can in turn contribute to the progression of chronic allograft nephropathy and allograft dysfunction.99,100 Treatment of HCV infection after kidney transplantation is challenging. Because antiviral therapy with interferon-a and ribavirin is generally contraindicated in kidney transplant recipients (because of the high risk of acute rejection during therapy), only a cautious reduction in overall immunosuppression may be considered in this setting. There are some isolated reports of rituximab administration in cases of mixed cryoglobulinemia, but no firm conclusions can be presented and rituximab may worsen HCV-associated liver disease.101 ADENOVIRUS

Adenoviral infections are a rare cause of graft dysfunction, with serotypes 11, 34, and 35 cited as the most frequent cause.102 The typical presentation is with fever, graft dysfunction, and hemorrhagic cystitis.102,103 Although there are case reports of successful antiviral treatment,104 robust evidence for efficacy is lacking. In contrast to hematopoietic stem cell transplantation, in which adenovirus infection can be life threatening, in most cases in solid organ transplant recipients the disease is self-limiting102,103 and no specific treatment is required. Median duration of illness is 3–4 weeks, with graft function returning to baseline in the majority of cases.103 PARVOVIRUS B19

Parvovirus B19 infection in the immune competent host is a benign self-limiting childhood illness manifesting as a Kidney International (2010) 78 (Suppl 119), S47–S53

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‘slapped cheek’ rash. In the immune-compromised host, it most often presents with a persistent anemia or pancytopenia105 that may be erroneously attributed to the immunosuppressive treatment. There are also a number of case reports in literature documenting allograft dysfunction due to parvovirus infection (as high as 15% in a recent review of 53 kidney transplant recipients with parvovirus infection106). Histological findings can include thrombotic microangiopathy,107 collapsing glomerulopathy,108 and segmental proliferative glomerular changes.109 In most cases, the viral infection is thought to be primary and donor derived.105,110 Treatment is generally associated with reduction of immunosuppression. Intravenous immunoglobulin has also been used with success.110,111 Graft loss due to parvovirus infection has been described,111 but most patients recover function.

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CONCLUSION

Although direct mortality and morbidity due to infectious diseases after organ transplantation has decreased over recent years, infection remains a significant factor for the development of chronic allograft dysfunction. Therefore, effective preventive strategies to decrease the incidence of posttransplant infections have the potential of improving the longterm outcomes of kidney allografts. In addition, it is clear now that the new immunosuppressive protocols currently under investigation should not only focus their efficacy to preventing acute rejection but also in minimizing drug toxicities and avoiding the development of infection.

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DISCLOSURE

PJD has received consulting fees from BMS. MP has declared no competing interests. OM has received consulting fees from Gilead and grant support from Roche.

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