*3.6.3 Biomarkers of BKN*

A plasma test by PCR detecting BK copies is currently the accepted biomarker for clinical application, although the exact range of viral load that would predict BKN cannot be defined. The majority of patients with more than 10,000 copies per ml DNA in 1 ml of plasma show BKN on renal biopsy, but some patients with hardly detectable BK virus copy numbers may have manifest BKN. Several studies have indicated that PCR-based BK viremia correlates only moderately well with the presence of BKN and severity of the intrarenal disease, ranging between 25 and 75% (**Figure 15**) [6, 57].

Several biomarkers had been proposed in order to enable noninvasive diagnosis of definitive BKN without the risk of renal biopsy; these include heat shock protein 90alfa, CXCL9, neutrophil gelatinase-associated lipocalin, urinary exosomal biomarkers, urinary VP1, and urinary Haufen [65–67].

Polyomavirus-Haufen are tight cast-like three-dimensional viral aggregates, detected by negative staining electron microscopy of a voided urine sample. Since polyomavirus-Haufen admixed with uromodulin is formed in the tubular lumens, they might specifically predict intrarenal disease, comparable to renal biopsy [68]. Recent studies have indicated that the titer of polyomavirus-Haufen tightly correlates with the degree of intrarenal polyomavirus replication, providing additional information on the severity of PVN [64]. The urinary polyomavirus-Haufen test may emerge as a sensitive and specific biomarker for intrarenal viral disease, with positive and negative predictive value higher than 90%. The limitations of this

#### *Perioperative Care for Organ Transplant Recipient*

investigation include the relatively high cost, time-consuming procedure, and limited availability of electron microscopy in transplant centers.

BK virus VP1 mRNA and urinary exosomal miRNA biomarkers have been described as potential surrogate markers for the diagnosis of PVN, with high sensitivity and specificity for BKN [66, 67]. Detection of additional urine biomarkers not only offers additional strategies for noninvasive PVN diagnosis but might also predict graft outcome.

#### *3.6.4 Treatment of BKN*

Management of PVN is still very limited. Reduction of the baseline immunosuppression, as the common therapeutic strategy, may be risky due to the possibility of acute rejection and may not be successful in all patients. Namely, some patients with BK viremia subsequently develop definitive BKN despite preemptive reduction of immunosuppression [4]. On the other hand, prolonged reduction of immunosuppression may be associated with clinical acute rejection rates of 8–14% [5, 69]. Renal biopsy, although considered to be an invasive procedure, may provide additional information in order to diagnose concomitant vascular rejection.

Data concerning the frequency of concurrent PVN and rejection vary. Some authors consider inflammation to be part of immune reconstitution injury, with a very low risk of concomitant rejection, whereas others have diagnosed concurrent acute rejection in 10–15% of cases at the time of initial PVN diagnosis [6, 47, 63]. Additional corticosteroid treatment in patients with PVN and severe tubulointerstitial inflammation at the time of PVN diagnosis also remains controversial. Some authors believe that corticosteroid treatment interferes with efficient BK clearance from the graft although, on the other hand, it might decrease interstitial inflammation and subsequent interstitial fibrosis [59].

Biopsy-proven diagnosis of concurrent BKN and rejection reveals the therapeutic dilemma concerning treatment strategy. In some individual cases, concomitant biopsy-proven T-cell-mediated rejection and PVN on low immunosuppression have been efficiently treated with transient pulse immunosuppressive therapy [70]. On surveillance kidney biopsy, BK was cleared from the tissue, interstitial inflammation disappeared, and serum creatinine returned to the baseline level.

Many of the therapeutic agents, including leflunomide, quinolone, and cidofovir, have been involved in BKN treatment with undetermined antipolyomavirus effect. It was recently shown that intravenous immunoglobulins' (IV IGs) administration may be effective in the treatment of BK viremia and PVN in patients who have failed to respond to immunosuppression reduction and leflunomide therapy [71].

Successful resolution of BKN and BK clearance may be associated with the recipient's antiviral cell-mediated immune response. Recently, novel laboratorybased methods based on BK-directed cellular immunity and anti-BK T-cell phenotype have been introduced, such as ELISPOT assays, which might provide additional information in relation to the resolution of PVN [72–74].

#### **4. Conclusions**

KTRs receiving immunosuppressive regimes to prevent transplant rejection are at increased risk of opportunistic infections such as CMV and polyoma BK virus. In both viruses, reactivation of latent infection is the principal mechanism rather than de novo infection.

**61**

provided the original work is properly cited.

*Viral Infections after Kidney Transplantation: CMV and BK*

development of overt nephropathy might be beneficial.

graft survival and quality of life in KTRs.

Authors declare no conflict of interest.

Večerić-Haler Željka\* and Kojc Nika

**Acknowledgements**

**Conflict of interest**

**Author details**

Slovenia

While reactivation of CMV infection is usually present with systemic infection, including fever, leukopenia, organ dysfunction, and viremia without invading renal graft, the most harmful presentation of BK infection reactivation includes BKN

Both CMV and BK infections commonly appear in the first year after transplantation, so screening protocols are very important in order to detect patients with increased risk of virus reactivation and early disease, and this should be started

The reduction of baseline immunosuppression is considered to be the common therapeutic strategy of BKN but is associated with increased risk of rejection. Since polyomavirus viruria and viremia can be observed without renal injury and BKN, a definite diagnosis of PVN must be confirmed by renal biopsy. In order to prevent BKN in viremic patients, preemptive reduction of immunosuppression prior to the

Careful detection and management of opportunistic infection enable better

The authors would like to acknowledge Jerica Pleško, Karmen Wechtersbach, Živa Pipan Tkalec, Špela Borštnar, MD, and Matic Bošnjak, MD for their valuable help with providing figure material for this chapter. Professor Danica Galešić Ljubanović, MD PhD and Petar Šenjug, MD provided figures of CMV nephritis.

With systematically quantitative monitoring of CMV DNA in plasma, CMV viremia can be detected before the occurrence of symptomatic infection. Ganciclovir and valganciclovir are generally used to prevent or treat CMV. For BKN screening, current guidelines recommend a urinary cytology test initially and then plasma DNA test by PCR if urinary decoy cells are consistently

*DOI: http://dx.doi.org/10.5772/intechopen.86043*

directly affecting the transplanted kidney.

immediately after transplantation.

found.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Department of Nephrology, University Medical Centre Ljubljana, Ljubljana,

\*Address all correspondence to: zeljka.vecerichaler@kclj.si

*Viral Infections after Kidney Transplantation: CMV and BK DOI: http://dx.doi.org/10.5772/intechopen.86043*

*Perioperative Care for Organ Transplant Recipient*

tion and subsequent interstitial fibrosis [59].

leflunomide therapy [71].

**4. Conclusions**

de novo infection.

predict graft outcome.

*3.6.4 Treatment of BKN*

rejection.

investigation include the relatively high cost, time-consuming procedure, and

BK virus VP1 mRNA and urinary exosomal miRNA biomarkers have been described as potential surrogate markers for the diagnosis of PVN, with high sensitivity and specificity for BKN [66, 67]. Detection of additional urine biomarkers not only offers additional strategies for noninvasive PVN diagnosis but might also

Management of PVN is still very limited. Reduction of the baseline immunosuppression, as the common therapeutic strategy, may be risky due to the possibility of acute rejection and may not be successful in all patients. Namely, some patients with BK viremia subsequently develop definitive BKN despite preemptive reduction of immunosuppression [4]. On the other hand, prolonged reduction of immunosuppression may be associated with clinical acute rejection rates of 8–14% [5, 69]. Renal biopsy, although considered to be an invasive procedure, may provide additional information in order to diagnose concomitant vascular

Data concerning the frequency of concurrent PVN and rejection vary. Some authors consider inflammation to be part of immune reconstitution injury, with a very low risk of concomitant rejection, whereas others have diagnosed concurrent acute rejection in 10–15% of cases at the time of initial PVN diagnosis [6, 47, 63]. Additional corticosteroid treatment in patients with PVN and severe tubulointerstitial inflammation at the time of PVN diagnosis also remains controversial. Some authors believe that corticosteroid treatment interferes with efficient BK clearance from the graft although, on the other hand, it might decrease interstitial inflamma-

Biopsy-proven diagnosis of concurrent BKN and rejection reveals the therapeutic dilemma concerning treatment strategy. In some individual cases, concomitant biopsy-proven T-cell-mediated rejection and PVN on low immunosuppression have been efficiently treated with transient pulse immunosuppressive therapy [70]. On surveillance kidney biopsy, BK was cleared from the tissue, interstitial inflamma-

tion disappeared, and serum creatinine returned to the baseline level.

additional information in relation to the resolution of PVN [72–74].

Many of the therapeutic agents, including leflunomide, quinolone, and cidofovir, have been involved in BKN treatment with undetermined antipolyomavirus effect. It was recently shown that intravenous immunoglobulins' (IV IGs) administration may be effective in the treatment of BK viremia and PVN in patients who have failed to respond to immunosuppression reduction and

Successful resolution of BKN and BK clearance may be associated with the recipient's antiviral cell-mediated immune response. Recently, novel laboratorybased methods based on BK-directed cellular immunity and anti-BK T-cell phenotype have been introduced, such as ELISPOT assays, which might provide

KTRs receiving immunosuppressive regimes to prevent transplant rejection are at increased risk of opportunistic infections such as CMV and polyoma BK virus. In both viruses, reactivation of latent infection is the principal mechanism rather than

limited availability of electron microscopy in transplant centers.

**60**

While reactivation of CMV infection is usually present with systemic infection, including fever, leukopenia, organ dysfunction, and viremia without invading renal graft, the most harmful presentation of BK infection reactivation includes BKN directly affecting the transplanted kidney.

Both CMV and BK infections commonly appear in the first year after transplantation, so screening protocols are very important in order to detect patients with increased risk of virus reactivation and early disease, and this should be started immediately after transplantation.

With systematically quantitative monitoring of CMV DNA in plasma, CMV viremia can be detected before the occurrence of symptomatic infection. Ganciclovir and valganciclovir are generally used to prevent or treat CMV.

For BKN screening, current guidelines recommend a urinary cytology test initially and then plasma DNA test by PCR if urinary decoy cells are consistently found.

The reduction of baseline immunosuppression is considered to be the common therapeutic strategy of BKN but is associated with increased risk of rejection. Since polyomavirus viruria and viremia can be observed without renal injury and BKN, a definite diagnosis of PVN must be confirmed by renal biopsy. In order to prevent BKN in viremic patients, preemptive reduction of immunosuppression prior to the development of overt nephropathy might be beneficial.

Careful detection and management of opportunistic infection enable better graft survival and quality of life in KTRs.

### **Acknowledgements**

The authors would like to acknowledge Jerica Pleško, Karmen Wechtersbach, Živa Pipan Tkalec, Špela Borštnar, MD, and Matic Bošnjak, MD for their valuable help with providing figure material for this chapter. Professor Danica Galešić Ljubanović, MD PhD and Petar Šenjug, MD provided figures of CMV nephritis.

#### **Conflict of interest**

Authors declare no conflict of interest.

## **Author details**

Večerić-Haler Željka\* and Kojc Nika Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia

\*Address all correspondence to: zeljka.vecerichaler@kclj.si

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
